Mutations in epigenetic regulatory genes are common in human cancers and are increasingly being recognized as attractive therapeutic targets.
Gain-of-function mutations and overexpression can be targeted by small molecule inhibitors. Inhibitors of EZH2, DOT1L, KDM1A, isocitrate dehydrogenase 1 (IDH1), IDH2 and bromodomain and extra-terminal (BET) family proteins have shown promise in clinical trials.
Loss-of-function mutations can be targeted through synthetic lethality. To date, potential therapies have been identified for cancers that are deficient in the switch/sucrose non-fermentable (SWI/SNF) complex, trimethylation of histone H3 lysine 36 (H3K36me3), CREB-binding protein (CBP), S-methyl-5′-thioadenosine phosphorylase (MTAP) and KDM6A.
Owing to their roles in immune modulation, epigenetic therapies can modulate the efficacy of immunotherapies.
Epigenetic inhibitors can also be used to overcome drug resistance.
Biological complexity, context dependency, inhibitor selectivity and biomarker selection should be considered during the development of new epigenetic therapies.
In the past few years, it has become clear that mutations in epigenetic regulatory genes are common in human cancers. Therapeutic strategies are now being developed to target cancers with mutations in these genes using specific chemical inhibitors. In addition, a complementary approach based on the concept of synthetic lethality, which allows exploitation of loss-of-function mutations in cancers that are not targetable by conventional methods, has gained traction. Both of these approaches are now being tested in several clinical trials. In this Review, we present recent advances in epigenetic drug discovery and development, and suggest possible future avenues of investigation to drive progress in this area.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
PGD2 displays distinct effects in diffuse large B-cell lymphoma depending on different concentrations
Cell Death Discovery Open Access 01 February 2023
A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer
Nature Communications Open Access 22 July 2022
MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF
Cancer Cell International Open Access 16 May 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K. & Schapira, M. Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11, 384–400 (2012).
Jones, P. A. & Laird, P. W. Cancer epigenetics comes of age. Nat. Genet. 21, 163–167 (1999).
Baylin, S. B. & Herman, J. G. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 16, 168–174 (2000).
Goelz, S. E., Vogelstein, B., Hamilton, S. R. & Feinberg, A. P. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228, 187–190 (1985).
Baylin, S. B. DNA methylation and gene silencing in cancer. Nat. Clin. Pract. Oncol. 2 (Suppl. 1), S4–S11 (2005).
Rhee, I. et al. DNMT1 and DNMT3B cooperate to silence genes in human cancer cells. Nature 416, 552–556 (2002).
Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003).
Howard, G., Eiges, R., Gaudet, F., Jaenisch, R. & Eden, A. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene 27, 404–408 (2008).
Jung, M. & Pfeifer, G. P. Aging and DNA methylation. BMC Biol. 13, 7 (2015).
Mizuno, S. et al. Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97, 1172–1179 (2001).
Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).
Langemeijer, S. M. et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat. Genet. 41, 838–842 (2009).
Abdel-Wahab, O. et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114, 144–147 (2009).
Ehrlich, M. DNA hypomethylation in cancer cells. Epigenomics 1, 239–259 (2009).
Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).
Lu, R. et al. Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell 30, 92–107 (2016).
Helming, K. C., Wang, X. & Roberts, C. W. Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 26, 309–317 (2014).
Li, W. & Mills, A. A. Architects of the genome: CHD dysfunction in cancer, developmental disorders and neurological syndromes. Epigenomics 6, 381–395 (2014).
Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).
Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014).
Vougiouklakis, T., Hamamoto, R., Nakamura, Y. & Saloura, V. The NSD family of protein methyltransferases in human cancer. Epigenomics 7, 863–874 (2015).
van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).
Konovalov, S. & Garcia-Bassets, I. Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines. J. Ovarian Res. 6, 75 (2013).
Berry, W. L. & Janknecht, R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 73, 2936–2942 (2013).
Glozak, M. A. & Seto, E. Histone deacetylases and cancer. Oncogene 26, 5420–5432 (2007).
Bischoff, J. R. et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 17, 3052–3065 (1998).
Hirota, T., Lipp, J. J., Toh, B. H. & Peters, J. M. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438, 1176–1180 (2005).
French, C. A. et al. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am. J. Pathol. 159, 1987–1992 (2001).
Tsai, W. W. et al. TRIM24 links a non-canonical histone signature to breast cancer. Nature 468, 927–932 (2010).
Groner, A. C. et al. TRIM24 is an oncogenic transcriptional activator in prostate cancer. Cancer Cell 29, 846–858 (2016).
Jia, Y. et al. Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer. Cell Discov. 2, 16007 (2016).
Fang, D. et al. The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science 352, 1344–1348 (2016).
Bender, S. et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24, 660–672 (2013).
Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).
Bjerke, L. et al. Histone H3.3 mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov. 3, 512–519 (2013).
Chan, K. M. et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985–990 (2013).
Liu, X., McEachron, T. A., Schwartzentruber, J. & Wu, G. Histone H3 mutations in pediatric brain tumors. Cold Spring Harb. Perspect. Biol. 6, a018689 (2014).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). This study shows the effect of IDH mutations on the epigenome.
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
Carbonneau, M. et al. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat. Commun. 7, 12700 (2016).
Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).
Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).
Wang, X. et al. Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Res. 69, 8094–8101 (2009).
Wilson, B. G. et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328 (2010).
Oike, T. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 73, 5508–5518 (2013).
Helming, K. C. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20, 251–254 (2014).
Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).
Wilson, B. G. et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol. Cell. Biol. 34, 1136–1144 (2014).
Bitler, B. G. et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231–238 (2015).
Kim, K. H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015). This study shows the synthetic lethal interaction between SWI/SNF componentdeficiency and EZH2 inhibition.
Pfister, S. X. et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28, 557–568 (2015). This study demonstrates the synthetic lethal interaction between H3K36me3 deficiency and checkpoint inhibition.
Yoo, C. B. & Jones, P. A. Epigenetic therapy of cancer: past, present and future. Nat. Rev. Drug Discov. 5, 37–50 (2006). This is a comprehensive review of DNMT and HDAC inhibitors.
Brueckner, B. et al. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res. 65, 6305–6311 (2005).
Sorm, F. & Vesely, J. The activity of a new antimetabolite, 5-azacytidine, against lymphoid leukaemia in ak mice. Neoplasma 11, 123–130 (1964).
Gnyszka, A., Jastrzebski, Z. & Flis, S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 33, 2989–2996 (2013).
Ramachandran, S., Ient, J., Gottgens, E. L., Krieg, A. J. & Hammond, E. M. Epigenetic therapy for solid tumors: highlighting the impact of tumor hypoxia. Genes (Basel) 6, 935–956 (2015).
Juergens, R. A. et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 1, 598–607 (2011).
Rocchi, P. et al. p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. Oncol. Rep. 13, 1139–1144 (2005).
Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).
Chen, L. F. & Greene, W. C. Regulation of distinct biological activities of the NF-κB transcription factor complex by acetylation. J. Mol. Med. (Berl.) 81, 549–557 (2003).
Mottamal, M., Zheng, S., Huang, T. L. & Wang, G. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 20, 3898–3941 (2015).
Mann, B. S., Johnson, J. R., Cohen, M. H., Justice, R. & Pazdur, R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T cell lymphoma. Oncologist 12, 1247–1252 (2007).
Lee, H. Z. et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T cell lymphoma. Clin. Cancer Res. 21, 2666–2670 (2015).
Bertino, E. M. & Otterson, G. A. Romidepsin: a novel histone deacetylase inhibitor for cancer. Expert Opin. Investig. Drugs 20, 1151–1158 (2011).
Xu, W. S., Parmigiani, R. B. & Marks, P. A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26, 5541–5552 (2007).
Qiu, T. et al. Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials. Future Oncol. 9, 255–269 (2013).
Héninger, E., Krueger, T. E. & Lang, J. M. Augmenting antitumor immune responses with epigenetic modifying agents. Front. Immunol. 6, 29 (2015).
Aymard, F. et al. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat. Struct. Mol. Biol. 21, 366–374 (2014).
Pfister, S. X. et al. SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 7, 2006–2018 (2014).
Carvalho, S. et al. SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint. eLife 3, e02482 (2014).
Fnu, S. et al. Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. Proc. Natl Acad. Sci. USA 108, 540–545 (2011).
Wagner, T. & Jung, M. New lysine methyltransferase drug targets in cancer. Nat. Biotechnol. 30, 622–623 (2012).
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).
Viré, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006).
Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).
Yap, D. B. et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459 (2011).
Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42, 722–726 (2010).
McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).
Xu, B. et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 125, 346–357 (2015).
Knutson, S. K. et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad. Sci. USA 110, 7922–7927 (2013).
Knutson, S. K. et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13, 842–854 (2014).
Woo Park, J. et al. RE-IIBP methylates H3K79 and induces MEIS1-mediated apoptosis via H2BK120 ubiquitination by RNF20. Sci. Rep. 5, 12485 (2015).
Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).
Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011).
Daigle, S. R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65 (2011).
Yu, W. et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat. Commun. 3, 1288 (2012).
Chen, L. et al. Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia 27, 813–822 (2013).
Daigle, S. R. et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122, 1017–1025 (2013).
Liu, W., Deng, L., Song, Y. & Redell, M. DOT1L inhibition sensitizes MLL-rearranged AML to chemotherapy. PLoS ONE 9, e98270 (2014).
Hui, C. & Ye, T. Synthesis of lysine methyltransferase inhibitors. Front. Chem. 3, 44 (2015).
Kubicek, S. et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25, 473–481 (2007).
Liu, F. et al. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J. Med. Chem. 56, 8931–8942 (2013).
Sweis, R. F. et al. Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. ACS Med. Chem. Lett. 5, 205–209 (2014).
Pappano, W. N. et al. The histone methyltransferase inhibitor A-366 uncovers a role for G9a/GLP in the epigenetics of leukemia. PLoS ONE 10, e0131716 (2015).
Agarwal, P. & Jackson, S. P. G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status. Cancer Lett. 380, 467–475 (2016).
Olsen, J. B. et al. Quantitative profiling of the activity of protein lysine methyltransferase SMYD2 using SILAC-based proteomics. Mol. Cell Proteom. 15, 892–905 (2016).
Ahmed, H., Duan, S., Arrowsmith, C. H., Barsyte-Lovejoy, D. & Schapira, M. An integrative proteomic approach identifies novel cellular SMYD2 substrates. J. Proteome Res. 15, 2052–2059 (2016).
Komatsu, S. et al. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 30, 1139–1146 (2009).
Nguyen, H. et al. LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2. J. Biol. Chem. 290, 13641–13653 (2015).
Eggert, E. et al. Discovery and characterization of a highly potent and selective aminopyrazoline-based in vivo probe (BAY-598) for the protein lysine methyltransferase SMYD2. J. Med. Chem. 59, 4578–4600 (2016).
Lv, T. et al. Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS ONE 7, e35065 (2012).
Serce, N. et al. Elevated expression of LSD1 (lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast. BMC Clin. Pathol. 12, 13 (2012).
Zhao, Z. K. et al. Overexpression of lysine specific demethylase 1 predicts worse prognosis in primary hepatocellular carcinoma patients. World J. Gastroenterol. 18, 6651–6656 (2012).
Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012).
Xiong, Y. et al. Inhibition of lysine-specific demethylase-1 (LSD1/KDM1A) promotes the adipogenic differentiation of hESCs through H3K4 methylation. Stem Cell Rev. 12, 298–304 (2016).
Harris, W. J. et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012).
Mohammad, H. P. et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell 28, 57–69 (2015).
Shi, L. et al. Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis. Proc. Natl Acad. Sci. USA 108, 7541–7546 (2011).
Coffey, K. et al. The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover. Nucleic Acids Res. 41, 4433–4446 (2013).
Hamada, S. et al. Synthesis and activity of N-oxalylglycine and its derivatives as jumonji C-domain-containing histone lysine demethylase inhibitors. Bioorg. Med. Chem. Lett. 19, 2852–2855 (2009).
Chu, C. H. et al. KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor. J. Med. Chem. 57, 5975–5985 (2014).
Chin, Y. W. & Han, S. Y. KDM4 histone demethylase inhibitors for anti-cancer agents: a patent review. Expert Opin. Ther. Pat. 25, 135–144 (2015).
French, C. A. et al. BRD4–NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 63, 304–307 (2003).
French, C. A. et al. BRD–NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27, 2237–2242 (2008).
Grayson, A. R. et al. MYC, a downstream target of BRD–NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene 33, 1736–1742 (2014).
French, C. A. small-molecule targeting of BET proteins in cancer. Adv. Cancer Res. 131, 21–58 (2016).
Pott, S. & Lieb, J. D. What are super-enhancers? Nat. Genet. 47, 8–12 (2015).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Stathis, A. et al. 5LBA results of a first-in-man phase I trial assessing OTX015, an orally available BET-bromodomain (BRD) inhibitor, in advanced hematologic malignancies. Eur. J. Cancer 50, 196 (2014).
Abramson, J. S. et al. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B-cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing phase 1 study. Blood 126, 1491 (2015).
Puissant, A. et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 3, 308–323 (2013).
Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011).
Yen, K. E., Bittinger, M. A., Su, S. M. & Fantin, V. R. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 29, 6409–6417 (2010).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011).
Caino, M. C. & Altieri, D. C. Molecular pathways: mitochondrial reprogramming in tumor progression and therapy. Clin. Cancer Res. 22, 540–545 (2016).
Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014).
Shih, L. Y. et al. Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement. Leukemia 20, 218–223 (2006).
Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).
Thiel, A. T. et al. MLL–AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 17, 148–159 (2010).
Cao, F. et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol. Cell 53, 247–261 (2014).
He, S. et al. High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction. J. Med. Chem. 57, 1543–1556 (2014).
Ashworth, A., Lord, C. J. & Reis-Filho, J. S. Genetic interactions in cancer progression and treatment. Cell 145, 30–38 (2011). This study is a comprehensive review on the application of synthetic lethality in cancer treatment.
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005). References 134 and 135 were the first studies to report the synthetic lethality between PARP inhibition and BRCA deficiency.
Hohmann, A. F. & Vakoc, C. R. A rationale to target the SWI/SNF complex for cancer therapy. Trends Genet. 30, 356–363 (2014).
Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).
Biegel, J. A. et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).
Roberts, C. W., Leroux, M. M., Fleming, M. D. & Orkin, S. H. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2, 415–425 (2002).
Klochendler-Yeivin, A. et al. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 1, 500–506 (2000).
Modena, P. et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 65, 4012–4019 (2005).
Trobaugh-Lotrario, A. D., Tomlinson, G. E., Finegold, M. J., Gore, L. & Feusner, J. H. Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr. Blood Cancer 52, 328–334 (2009).
Kreiger, P. A. et al. Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas. Mod. Pathol. 22, 142–150 (2009).
Kennison, J. A. & Tamkun, J. W. Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila. Proc. Natl Acad. Sci. USA 85, 8136–8140 (1988).
Tamkun, J. W. et al. Brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561–572 (1992).
Kennison, J. A. The Polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function. Annu. Rev. Genet. 29, 289–303 (1995).
Shao, Z. et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98, 37–46 (1999).
Kia, S. K., Gorski, M. M., Giannakopoulos, S. & Verrijzer, C. P. SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus. Mol. Cell. Biol. 28, 3457–3464 (2008).
Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).
Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).
Kim, W. et al. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat. Chem. Biol. 9, 643–650 (2013).
Penebre, E. et al. Preclinical and clinical evaluation of EZH2 inhibitors in models of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Epizyme http://www.epizyme.com/wp-content/uploads/2016/03/11-10-2105-SCCOHT-poster-for-review-finala.pdf (2015).
Reisman, D. N., Sciarrotta, J., Wang, W., Funkhouser, W. K. & Weissman, B. E. Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res. 63, 560–566 (2003).
Romero, O. A. et al. MAX inactivation in small cell lung cancer disrupts MYC–SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov. 4, 292–303 (2014).
Wang, K. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 43, 1219–1223 (2011).
Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011).
Guichard, C. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44, 694–698 (2012).
Hodis, E. et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012).
Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013).
Shain, A. H. & Pollack, J. R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS ONE 8, e55119 (2013).
Shen, J. et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 5, 752–767 (2015).
Williamson, C. T. et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat. Commun. 7, 13837 (2016).
Samartzis, E. P. et al. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget 5, 5295–5303 (2014).
Miller, R. E. et al. Synthetic lethal targeting of ARID1A-mutant ovarian clear cell tumors with dasatinib. Mol. Cancer Ther. 15, 1472–1484 (2016).
Vangamudi, B. et al. The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNF-mutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res. 75, 3865–3878 (2015).
Winter, G. E. et al. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
Duns, G. et al. Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma. Cancer Res. 70, 4287–4291 (2010).
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Fontebasso, A. M. et al. Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathol. 125, 659–669 (2013).
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 6, pl1 (2013).
Al Sarakbi, W. et al. The mRNA expression of SETD2 in human breast cancer: correlation with clinico-pathological parameters. BMC Cancer 9, 290 (2009).
Black, J. C. et al. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 154, 541–555 (2013).
Hakimi, A. A. et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin. Cancer Res. 19, 3259–3267 (2013).
Park, I. Y. et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166, 950–962 (2016).
Kishimoto, M. et al. Mutations and deletions of the CBP gene in human lung cancer. Clin. Cancer Res. 11, 512–519 (2005).
Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).
Mullighan, C. G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).
Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011).
Ojesina, A. I. et al. Landscape of genomic alterations in cervical carcinomas. Nature 506, 371–375 (2014).
Le Gallo, M. et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat. Genet. 44, 1310–1315 (2012).
Xu, W. et al. Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cells. Blood 107, 4407–4416 (2006).
Kasper, L. H. et al. Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T cell development. Mol. Cell. Biol. 26, 789–809 (2006).
Stauffer, D. Chang, B., Huang, J., Dunn, A. & Thayer, M. p300/CREB-binding protein interacts with ATR and is required for the DNA replication checkpoint. J. Biol. Chem. 282, 9678–9687 (2007).
Ogiwara, H. et al. Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression. Cancer Discov. 6, 430–445 (2016).
Bedford, D. C., Kasper, L. H., Fukuyama, T. & Brindle, P. K. Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases. Epigenetics 5, 9–15 (2010).
Kadoch, C. Lifting up the HAT: synthetic lethal screening reveals a novel vulnerability at the CBP-p300 axis. Cancer Discov. 6, 350–352 (2016).
Stopa, N., Krebs, J. E. & Shechter, D. The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell. Mol. Life Sci. 72, 2041–2059 (2015).
Jin, Y. et al. Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia. J. Clin. Invest. (2016).
Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).
Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).
Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016).
Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016). References 193–195 demonstrate the synthetic lethal interaction between MTAP deficiency and PRMT5 inhibition.
Van der Meulen, J. et al. The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T cell acute lymphoblastic leukemia. Blood 125, 13–21 (2015).
Ezponda, T. et al. Loss of the histone demethylase UTX contributes to multiple myeloma and sensitizes cells to EZH2 inhibitors. Blood 124, 611 (2014).
Hashizume, R. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394–1396 (2014).
Chan, D. A. & Giaccia, A. J. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat. Rev. Drug Discov. 10, 351–364 (2011).
Gilbert, L. A. et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159, 647–661 (2014).
Shi, J. et al. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains. Nat. Biotechnol. 33, 661–667 (2015). This study describes a useful tool for finding epigenetic protein targets using CRISPR–Cas9.
Blomen, V. A. et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015).
Guo, J., Liu, H. & Zheng, J. SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets. Nucleic Acids Res. 44, D1011–D1017 (2016).
Iorio, F. et al. A landscape of pharmacogenomic interactions in cancer. Cell 166, 740–754 (2016). This reference outlines a useful tool for the study of drug–gene interactions.
Roguev, A. et al. Conservation and rewiring of functional modules revealed by an epistasis map in fission yeast. Science 322, 405–410 (2008).
Kuzmin, E., Costanzo, M., Andrews, B. & Boone, C. Synthetic genetic array analysis. Cold Spring Harb. Protoc. http://dx.doi.org/10.1101/pdb.prot088807 (2016).
Lucchesi, J. C. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanogaster. Genetics 59, 37–44 (1968).
Jha, D. K., Pfister, S. X., Humphrey, T. C. & Strahl, B. D. SET-ting the stage for DNA repair. Nat. Struct. Mol. Biol. 21, 655–657 (2014).
Pai, C. C. et al. A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice. Nat. Commun. 5, 4091 (2014).
Tomasi, T. B., Magner, W. J. & Khan, A. N. Epigenetic regulation of immune escape genes in cancer. Cancer Immunol. Immunother. 55, 1159–1184 (2006).
Blankenstein, T., Coulie, P. G., Gilboa, E. & Jaffee, E. M. The determinants of tumour immunogenicity. Nat. Rev. Cancer 12, 307–313 (2012).
Khan, A. N., Magner, W. J. & Tomasi, T. B. An epigenetically altered tumor cell vaccine. Cancer Immunol. Immunother. 53, 748–754 (2004).
Setiadi, A. F. et al. Epigenetic control of the immune escape mechanisms in malignant carcinomas. Mol. Cell. Biol. 27, 7886–7894 (2007).
Maio, M., Coral, S., Fratta, E., Altomonte, M. & Sigalotti, L. Epigenetic targets for immune intervention in human malignancies. Oncogene 22, 6484–6488 (2003).
Yu, J. et al. Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer 4, 65 (2004).
Simpson, A. J., Caballero, O. L., Jungbluth, A., Chen, Y. T. & Old, L. J. Cancer/testis antigens, gametogenesis and cancer. Nat. Rev. Cancer 5, 615–625 (2005).
Rao, M. et al. Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer. Cancer Res. 71, 4192–4204 (2011).
Matheson, L. S. & Corcoran, A. E. Local and global epigenetic regulation of V(D)J recombination. Curr. Top. Microbiol. Immunol. 356, 65–89 (2012).
Serrano, A. et al. Rexpression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2′-deoxycytidine treatment. Int. J. Cancer 94, 243–251 (2001).
Karpf, A. R. A potential role for epigenetic modulatory drugs in the enhancement of cancer/germ-line antigen vaccine efficacy. Epigenetics 1, 116–120 (2006).
Odunsi, K. et al. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol. Res. 2, 37–49 (2014).
Srivastava, P. et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk. Res. 38, 1332–1341 (2014).
Konkankit, V. V. et al. Decitabine immunosensitizes human gliomas to NY-ESO-1 specific T lymphocyte targeting through the Fas/Fas ligand pathway. J. Transl. Med. 9, 192 (2011).
Karpf, A. R. et al. Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc. Natl Acad. Sci. USA 96, 14007–14012 (1999).
Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015). References 225 and 226 demonstrate the effect of DNA methylation on the immune response.
Kopp, L. M. et al. Decitabine has a biphasic effect on natural killer cell viability, phenotype, and function under proliferative conditions. Mol. Immunol. 54, 296–301 (2013).
West, A. C., Smyth, M. J. & Johnstone, R. W. The anticancer effects of HDAC inhibitors require the immune system. Oncoimmunology 3, e27414 (2014).
Gameiro, S. R., Malamas, A. S., Tsang, K. Y., Ferrone, S. & Hodge, J. W. Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T cell mediated lysis of prostate and breast carcinoma cells. Oncotarget 7, 7390–7402 (2016).
Zheng, H. et al. HDAC inhibitors enhance T cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 22, 4119–4132 (2016).
Maeda, T., Towatari, M., Kosugi, H. & Saito, H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 96, 3847–3856 (2000).
Magner, W. J. et al. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J. Immunol. 165, 7017–7024 (2000).
Chou, S. D., Khan, A. N., Magner, W. J. & Tomasi, T. B. Histone acetylation regulates the cell type specific CIITA promoters, MHC class II expression and antigen presentation in tumor cells. Int. Immunol. 17, 1483–1494 (2005).
Shen, L. et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS ONE 7, e30815 (2012).
Armeanu, S. et al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 65, 6321–6329 (2005).
Skov, S. et al. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B. Cancer Res. 65, 11136–11145 (2005).
Nagarsheth, N. et al. PRC2 epigenetically silences Th1-type chemokines to suppress effector T-Cell trafficking in colon cancer. Cancer Res. 76, 275–282 (2016).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015). This study demonstrates that epigenetic inhibitors can improve the efficacy of immunotherapy.
Zhu, H. et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep. 16, 2829–2837 (2016). This study shows the effect of BET inhibitors on PDL1 expression.
Wrangle, J. et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4, 2067–2079 (2013).
Yang, H. et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28, 1280–1288 (2014).
Woods, D. M. et al. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol. Res. 3, 1375–1385 (2015).
Kim, K. et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111, 11774–11779 (2014).
Kunert, A. et al. MAGE-C2-specific TCRs combined with epigenetic drug-enhanced antigenicity yield robust and tumor-selective T cell responses. J. Immunol. 197, 2541–2552 (2016).
Falchi, L. et al. High rate of complete responses to immune checkpoint inhibitors in patients with relapsed or refractory Hodgkin lymphoma previously exposed to epigenetic therapy. J. Hematol. Oncol. 9, 132 (2016).
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
Vinogradova, M. et al. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat. Chem. Biol. 12, 531–538 (2016).
Rathert, P. et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525, 543–547 (2015).
Fong, C. Y. et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 525, 538–542 (2015).
Shu, S. et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529, 413–417 (2016).
Settleman, J. Cancer: Bet on drug resistance. Nature 529, 289–290 (2016).
Yuen, B. T. & Knoepfler, P. S. Histone H3.3 mutations: a variant path to cancer. Cancer Cell 24, 567–574 (2013).
Deb, G., Singh, A. K. & Gupta, S. EZH2: not EZHY (easy) to deal. Mol. Cancer Res. 12, 639–653 (2014).
Woon, E. C. et al. Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases. Angew. Chem. Int. Ed. 51, 1631–1634 (2012).
Kanai, Y., Ushijima, S., Nakanishi, Y., Sakamoto, M. & Hirohashi, S. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer Lett. 192, 75–82 (2003).
Yan, X. J. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 43, 309–315 (2011).
Walter, M. J. et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25, 1153–1158 (2011).
Couronné, L., Bastard, C. & Bernard, O. A. TET2 and DNMT3A mutations in human T cell lymphoma. N. Engl. J. Med. 366, 95–96 (2012).
Kim, M. S., Kim, Y. R., Yoo, N. J. & Lee, S. H. Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers. APMIS 121, 85–94 (2013).
Jin, F. et al. Up-regulation of DNA methyltransferase 3B expression in endometrial cancers. Gynecol. Oncol. 96, 531–538 (2005).
Dolnik, A. et al. Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing. Blood 120, e83–e92 (2012).
Scourzic, L., Mouly, E. & Bernard, O. A. TET proteins and the control of cytosine demethylation in cancer. Genome Med. 7, 9 (2015).
Shain, A. H. et al. Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc. Natl Acad. Sci. USA 109, E252–E259 (2012).
Sausen, M. et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat. Genet. 45, 12–17 (2013).
Li, M. et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. 43, 828–829 (2011).
Manceau, G. et al. Recurrent inactivating mutations of ARID2 in non-small cell lung carcinoma. Int. J. Cancer 132, 2217–2221 (2013).
Yan, Z. et al. PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes. Genes Dev. 19, 1662–1667 (2005).
Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).
Fujimoto, A. et al. Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. Nat. Commun. 6, 6120 (2015).
Love, C. et al. The genetic landscape of mutations in Burkitt lymphoma. Nat. Genet. 44, 1321–1325 (2012).
Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).
Robinson, G. et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 488, 43–48 (2012).
Glaros, S. et al. The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26, 7058–7066 (2007).
Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).
Smith, M. J. et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat. Genet. 45, 295–298 (2013).
Kolla, V., Zhuang, T., Higashi, M., Naraparaju, K. & Brodeur, G. M. Role of CHD5 in human cancers: 10 years later. Cancer Res. 74, 652–658 (2014).
Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).
Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).
Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199–1203 (2011).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Thirman, M. J. et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N. Engl. J. Med. 329, 909–914 (1993).
Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer 7, 823–833 (2007).
Rao, R. C. & Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer 15, 334–346 (2015).
Lee, W. et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1227–1232 (2014).
Zhang, J. et al. The genetic basis of early T cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Morishita, M. & di Luccio, E. Cancers and the NSD family of histone lysine methyltransferases. Biochim. Biophys. Acta 1816, 158–163 (2011).
Pajtler, K. W. et al. The KDM1A histone demethylase is a promising new target for the epigenetic therapy of medulloblastoma. Acta Neuropathol. Commun. 1, 19 (2013).
Heidenblad, M. et al. Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors. BMC Med. Genom. 1, 3 (2008).
Tzatsos, A. et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J. Clin. Invest. 123, 727–739 (2013).
Hou, J. et al. Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer. Am. J. Transl. Res. 4, 247–256 (2012).
van Zutven, L. J. et al. Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes Chromosomes Cancer 45, 437–446 (2006).
Pereira, B. et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat. Commun. 7, 11479 (2016).
Tang, B. et al. JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells. Oncotarget 6, 12723–12739 (2015).
Yamamoto, K. et al. Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. Carcinogenesis 35, 2404–2414 (2014).
Anderton, J. A. et al. The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin's Lymphoma. Oncogene 30, 2037–2043 (2011).
Adams, H., Fritzsche, F. R., Dirnhofer, S., Kristiansen, G. & Tzankov, A. Class I histone deacetylases 1, 2 and 3 are highly expressed in classical Hodgkin's lymphoma. Expert Opin. Ther. Targets 14, 577–584 (2010).
Fritzsche, F. R. et al. Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer 8, 381 (2008).
Hanigan, C. L. et al. An inactivating mutation in HDAC2 leads to dysregulation of apoptosis mediated by APAF1. Gastroenterology 135, 1654–1664.e2 (2008).
Ropero, S. et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat. Genet. 38, 566–569 (2006).
Oehme, I. et al. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin. Cancer Res. 15, 91–99 (2009).
Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).
Moreno, D. A. et al. Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br. J. Haematol. 150, 665–673 (2010).
Milde, T. et al. HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth. Clin. Cancer Res. 16, 3240–3252 (2010).
Borrow, J. et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat. Genet. 14, 33–41 (1996).
Gorrini, C. et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063–1067 (2007).
Zhang, P. et al. BRD4 promotes tumor growth and epithelial–mesenchymal transition in hepatocellular carcinoma. Int. J. Immunopathol. Pharmacol. 28, 36–44 (2015).
Goundiam, O. et al. Histo-genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non-BRCAness high grade ovarian carcinoma. Int. J. Cancer 137, 1890–1900 (2015).
Peña, P. V. et al. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol. 380, 303–312 (2008).
Van Vlierberghe, P. et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia 25, 130–134 (2011).
Amary, M. F. et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334–343 (2011).
Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).
Kosmider, O. et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24, 1094–1096 (2010).
Balss, J. et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 116, 597–602 (2008).
Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).
Hemerly, J. P., Bastos, A. U. & Cerutti, J. M. Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur. J. Endocrinol. 163, 747–755 (2010).
Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002).
Letouzé, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013).
Bardella, C., Pollard, P. J. & Tomlinson, I. SDH mutations in cancer. Biochim. Biophys. Acta 1807, 1432–1443 (2011).
We thank members of the Ashworth laboratory, J. Esensten and J. Gordan for their helpful comments on the manuscript. Work in the Ashworth laboratory is supported by the US National Cancer Institute, Breast Cancer Research Foundation, S.G. Komen for the Cure and the BRCA Foundation.
S.X.P. declares no competing interests. A.A. has patents on the use of PARP inhibitors held jointly with AstraZeneca and has benefitted financially (and may do so in the future) through the ICR Rewards to Inventors Scheme. A.A. is also a co-founder of Tango Therapeutics.
Decreased methylation on DNA or histones. DNA hypomethylation usually occurs at repeated sequences of the genome and can result in genome instability and transcriptional alteration.
Increased methylation on DNA or histones. DNA hypermethylation at gene promoters can result in transcriptional silencing.
Enzymes that remove methyl groups from nucleic acids, proteins and other molecules.
Enzymes that add methyl groups to nucleic acids, proteins and other molecules. Both DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs) use S-adenosylmethionine (SAM) as the methyl donor, and many HMT inhibitors are SAM-competitive.
- Histone H3.3
A histone H3 variant that is deposited at actively transcribed regions of chromatin. It is encoded by one of the two genes, H3F3A or H3F3B.
- Immune checkpoint inhibitors
Inhibitors against immune checkpoint proteins that keep immune responses in check and prevent T cells from killing cancer cells. These inhibitors are used in cancer treatments. Examples of targets include programmed cell death protein 1 (PD1)–programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4)–B7-1 (also known as CTLA4–CD80) or CTLA4–B7-2 (also known as CTLA4–CD83).
- Mono-, di- or trimethylation
(Denoted by me, me2 and me3). They represent the number of methyl groups on the lysine and arginine residues. Lysine residue can be mono-, di- or trimethylated, whereas arginine can be mono- or dimethylated.
- Polycomb repressive complex 2
(PRC2). A Polycomb complex responsible for the di- and trimethylation of histone H3 lysine 27 (H3K27). The PRC2 core complex consists of EZH2, EED, SUZ12, RBBP7 and RBBP4.
- Cancer testis antigens
A large family (with approximately 140 members) of tumour-associated antigens, which are expressed in various cancer types but not in normal tissues (except in the testis and placenta). They are usually highly immunogenic and are good immunotherapeutic targets.
- Adoptive T cell therapy
A personalized cancer therapy that involves tumour-specific T cell isolation, ex vivo expansion and infusion into the same patient. The infused T cells can be naturally occurring tumour-reactive lymphocytes that were isolated from tumour-infiltrating lymphocytes (TILs), genetically engineered T cells expressing antitumour T cell receptors (TCRs) or chimeric antigen receptors (CARs).
Rights and permissions
About this article
Cite this article
Pfister, S., Ashworth, A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov 16, 241–263 (2017). https://doi.org/10.1038/nrd.2016.256
This article is cited by
PGD2 displays distinct effects in diffuse large B-cell lymphoma depending on different concentrations
Cell Death Discovery (2023)
Altered pathways and targeted therapy in double hit lymphoma
Journal of Hematology & Oncology (2022)
MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF
Cancer Cell International (2022)
A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer
Nature Communications (2022)
PROTAC: targeted drug strategy. Principles and limitations
Russian Chemical Bulletin (2022)