Key Points
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There is strong evidence that members of the histone lysine demethylase families are causally linked to cancer and they are therefore considered as potential targets for small-molecule therapeutics.
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Lysine-specific demethylase 1 (LSD1) is required for the maintenance of acute myeloid leukaemia. Jumonji domain-containing protein 2B (JMJD2B), JMJD2C, Jumonji/ARID domain-containing protein 1B (JARID1B) and F-box and leucine-rich repeat protein 10 (FBXL10) are overexpressed in several cancers and are required for the growth of cancer cell lines.
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The therapeutic potential of selective demethylase inhibitors has been demonstrated in animal models of cancer through the administration of available demethylase inhibitors or knockdown strategies.
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Nonselective amine oxidase inhibitors have been derived to yield potent and selective LSD1 inhibitors, and clinical trials will soon be initiated.
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Potent and subfamily-selective Jumonji C (JMJC) domain-containing demethylase inhibitors have emerged and provide optimism that true drug leads targeting this protein family are attainable.
Abstract
It has recently been demonstrated that the genes controlling the epigenetic programmes that are required for maintaining chromatin structure and cell identity include genes that drive human cancer. This observation has led to an increased awareness of chromatin-associated proteins as potentially interesting drug targets. The successful introduction of DNA methylation and histone deacetylase (HDAC) inhibitors for the treatment of specific subtypes of cancer has paved the way for the use of epigenetic therapy. Here, we highlight key biological findings demonstrating the roles of members of the histone lysine demethylase class of enzymes in the development of cancers, discuss the potential and challenges of therapeutically targeting them, and highlight emerging small-molecule inhibitors of these enzymes.
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References
You, J. S. & Jones, P. A. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22, 9–20 (2012).
Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genet. 44, 251–253 (2012).
Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012). References 2 and 4 report on driver mutations in H3.3, which affect K27 and G24 in paediatric glioblastoma.
Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K. & Schapira, M. Epigenetic protein families: a new frontier for drug discovery. Nature Rev. Drug Discov. 11, 384–400 (2012).
Wigle, T. J. & Copeland, R. A. Drugging the human methylome: an emerging modality for reversible control of aberrant gene transcription. Curr. Opin. Chem. Biol. 17, 369–378 (2013).
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).
Black, J. C., Van Rechem, C. & Whetstine, J. R. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell 48, 491–507 (2012).
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).
Varambally, S. et al. The Polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).
Bracken, A. P. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003).
Hudlebusch, H. R. et al. MMSET is highly expressed and associated with aggressiveness in neuroblastoma. Cancer Res. 71, 4226–4235 (2011).
Wang, P. et al. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol. Cell. Biol. 29, 6074–6085 (2009).
Dorrance, A. M. et al. The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele. Blood 112, 2508–2511 (2008).
Dorrance, A. M. et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J. Clin. Invest. 116, 2707–2716 (2006).
Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).
Albert, M. & Helin, K. Histone methyltransferases in cancer. Semin. Cell Dev. Biol. 21, 209–220 (2010).
Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nature Rev. Genet. 13, 343–357 (2012).
Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).
Jiang, H. et al. Role for Dpy-30 in ES cell-fate specification by regulation of H3K4 methylation within bivalent domains. Cell 144, 513–525 (2011).
Pasini, D., Bracken, A. P., Jensen, M. R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061–4071 (2004).
Margueron, R. et al. Role of the Polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009).
Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).
Kouzarides, T. SnapShot: Histone-modifying enzymes. Cell 131, 822 (2007).
Yun, M., Wu, J., Workman, J. L. & Li, B. Readers of histone modifications. Cell Res. 21, 564–578 (2011).
Zhang, Z. & Pugh, B. F. High-resolution genome-wide mapping of the primary structure of chromatin. Cell 144, 175–186 (2011).
Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet. 27, 389–396 (2011).
Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).
Tsukada, Y.-i. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).
Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).
Klose, R. J. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442, 312–316 (2006).
Cloos, P. A. C. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).
Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).
Kooistra, S. M. & Helin, K. Molecular mechanisms and potential functions of histone demethylases. Nature Rev. Mol. Cell Biol. 13, 297–311 (2012).
Zee, B. M. et al. In vivo residue-specific histone methylation dynamics. J. Biol. Chem. 285, 3341–3350 (2010).
Barth, T. K. & Imhof, A. Fast signals and slow marks: the dynamics of histone modifications. Trends Biochem. Sci. 35, 618–626 (2010).
Karytinos, A. et al. A novel mammalian flavin-dependent histone demethylase. J. Biol. Chem. 284, 17775–17782 (2009).
Fitzpatrick, P. F. Oxidation of amines by flavoproteins. Arch. Biochem. Biophys. 493, 13–25 (2010).
Aravind, L. & Iyer, L. M. The SWIRM domain: a conserved module found in chromosomal proteins points to novel chromatin-modifying activities. Genome Biol. 3, research0039 (2002).
Forneris, F., Binda, C., Vanoni, M. A., Mattevi, A. & Battaglioli, E. Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process. FEBS Lett. 579, 2203–2207 (2005).
Chen, Y. et al. Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc. Natl Acad. Sci. USA 103, 13956–13961 (2006). This structural characterization of LSD1 and its comparison with related amine oxidases is of considerable value in the design of selective inhibitors.
Forneris, F., Binda, C., Adamo, A., Battaglioli, E. & Mattevi, A. Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J. Biol. Chem. 282, 20070–20074 (2007).
Fang, R. et al. LSD2/KDM1B and its cofactor NPAC/GLYR1 endow a structural and molecular model for regulation of H3K4 demethylation. Mol. Cell 49, 558–570 (2013).
Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).
Huang, J. et al. p53 is regulated by the lysine demethylase LSD1. Nature 449, 105–108 (2007).
Kontaki, H. & Talianidis, I. Lysine methylation regulates E2F1-induced cell death. Mol. Cell 39, 152–160 (2010).
Wang, J. et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nature Genet. 41, 125–129 (2009).
Yoneyama, M. et al. Structural and functional differences of SWIRM domain subtypes. J. Mol. Biol. 369, 222–238 (2007).
Chen, F. et al. Structural insight into substrate recognition by histone demethylase LSD2/KDM1b. Cell Res. 23, 306–309 (2013).
Zhang, Q. et al. Structure-function analysis reveals a novel mechanism for regulation of histone demethylase LSD2/AOF1/KDM1b. Cell Res. 23, 225–241 (2013).
Lee, M. G., Wynder, C., Cooch, N. & Shiekhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432–435 (2005).
Shi, Y.-J. et al. Regulation of LSD1 histone demethylase activity by its associated factors. Mol. Cell 19, 857–864 (2005).
Yang, M. et al. Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol. Cell 23, 377–387 (2006).
Hausinger, R. P. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit. Rev. Biochem. Mol. Biol. 39, 21–68 (2004).
McDonough, M. A., Loenarz, C., Chowdhury, R., Clifton, I. J. & Schofield, C. J. Structural studies on human 2-oxoglutarate dependent oxygenases. Curr. Opin. Struct. Biol. 20, 659–672 (2010).
Iyer, L. M., Abhiman, S., de Souza, R. F. & Aravind, L. Origin and evolution of peptide-modifying dioxygenases and identification of the wybutosine hydroxylase/hydroperoxidase. Nucleic Acids Res. 38, 5261–5279 (2010).
Hegg, E. L. & Que, L. The 2-His-1-carboxylate facial triad — an emerging structural motif in mononuclear non-heme iron(II) enzymes. Eur. J. Biochem. 250, 625–629 (1997).
Klose, R. J., Kallin, E. M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nature Rev. Genet. 7, 715–727 (2006).
Horton, J. R., Upadhyay, A. K., Hashimoto, H., Zhang, X. & Cheng, X. Structural basis for human PHF2 Jumonji domain interaction with metal ions. J. Mol. Biol. 406, 1–8 (2011).
Stender, J. D. et al. Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. Mol. Cell 48, 28–38 (2012).
Wen, H. et al. Recognition of histone H3K4 trimethylation by the plant homeodomain of PHF2 modulates histone demethylation. J. Biol. Chem. 285, 9322–9326 (2010).
Baba, A. et al. PKA-dependent regulation of the histone lysine demethylase complex PHF2–ARID5B. Nature Cell Biol. 13, 668–675 (2011).
Del Rizzo, P. A., Krishnan, S. & Trievel, R. C. Crystal structure and functional analysis of JMJD5 indicate an alternate specificity and function. Mol. Cell. Biol. 32, 4044–4052 (2012).
Webby, C. J. et al. Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 325, 90–93 (2009).
Ng, S. S. et al. Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 448, 87–91 (2007).
Chen, Z. et al. Structural basis of the recognition of a methylated histone tail by JMJD2A. Proc. Natl Acad. Sci. USA 104, 10818–10823 (2007).
Couture, J.-F., Collazo, E., Ortiz-Tello, P. A., Brunzelle, J. S. & Trievel, R. C. Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nature Struct. Mol. Biol. 14, 689–695 (2007).
Krishnan, S. & Trievel, R. C. Structural and functional analysis of JMJD2D reveals molecular basis for site-specific demethylation among JMJD2 demethylases. Structure 21, 98–108 (2013). This paper identifies enzyme–substrate interactions that are important for substrate specificity in a subfamily of JMJC domain-containing demethylases.
Horton, J. R. et al. Enzymatic and structural insights for substrate specificity of a family of Jumonji histone lysine demethylases. Nature Struct. Mol. Biol. 17, 38–43 (2010).
Yan, J. et al. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood 121, 4512–4520 (2013).
Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).
Yan, L. et al. Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification. Haematologica 97, 1708–1712 (2012).
Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).
Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nature Genet. 43, 875–878 (2011).
van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009). This is the first paper to identify somatic mutations in a histone demethylase in cancer.
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. 463, 360–363 (2010).
Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genet. 42, 181–185 (2010).
Hayami, S. et al. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int. J. Cancer 128, 574–586 (2011).
Kauffman, E. C. et al. Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Mol. Carcinog. 50, 931–944 (2011).
Kahl, P. et al. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res. 66, 11341–11347 (2006).
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).
Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nature Med. 18, 605–611 (2012). References 82 and 83 provide evidence for a causal role of LSD1 in AML and explore the therapeutic efficacy of a specific LSD1 inhibitor in an animal model of cancer.
Oryzon Genomics S. A. Phenylcyclopropylamine derivatives and their medical use. WO2010084160A1 (2010).
Yang, Z.-Q. et al. Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines. Cancer Res. 60, 4735–4739 (2000).
Liu, G. et al. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28, 4491–4500 (2009).
Ehrbrecht, A. et al. Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J. Pathol. 208, 554–563 (2006).
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).
Kawazu, M. et al. Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development. PloS ONE 6, e17830 (2011).
Yang, J. et al. The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth. Cancer Res. 70, 6456–6466 (2010).
Fu, L. et al. HIF-1α-induced histone demethylase JMJD2B contributes to the malignant phenotype of colorectal cancer cells via an epigenetic mechanism. Carcinogenesis 33, 1664–1673 (2012).
Wissmann, M. et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nature Cell Biol. 9, 347–353 (2007).
Rui, L. et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 18, 590–605 (2010).
Albert, M. et al. The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3. PLoS Genet. 9, e1003461 (2013).
Schmitz, S. U. et al. Jarid1b targets genes regulating development and is involved in neural differentiation. EMBO J. 30, 4586–4600 (2011).
Lu, P. J. et al. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically up-regulated in breast cancer. J. Biol. Chem. 274, 15633–15645 (1999).
Barrett, A. et al. PLU-1 nuclear protein, which is upregulated in breast cancer, shows restricted expression in normal human adult tissues: a new cancer/testis antigen? Int. J. Cancer 101, 581–588 (2002).
Hayami, S. et al. Overexpression of the JmjC histone demethylase KDM5B in human carcinogenesis: involvement in the proliferation of cancer cells through the E2F/RB pathway. Mol. Cancer 9, 59 (2010).
Xiang, Y. et al. JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc. Natl Acad. Sci. USA 104, 19226–19231 (2007).
Yamane, K. et al. PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol. Cell 25, 801–812 (2007).
Roesch, A. et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141, 583–594 (2010). This paper provides evidence that JARID1B is required for the growth of slow-cycling melanoma cells.
Wu, X., Johansen, J. V. & Helin, K. Fbxl10/Kdm2b recruits Polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol. Cell 49, 1134–1146 (2013).
He, J., Nguyen, A. T. & Zhang, Y. KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood 117, 3869–3880 (2011).
Tzatsos, A. et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J. Clin. Invest. 123, 727–739 (2013).
Farcas, A. M. et al. KDM2B links the Polycomb repressive complex 1 (PRC1) to recognition of CpG islands. eLIFE 1, e00205 (2012).
Lee, M. G., Wynder, C., Schmidt, D. M., McCafferty, D. G. & Shiekhattar, R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13, 563–567 (2006).
Schmidt, D. M. Z. & McCafferty, D. G. trans-2-phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46, 4408–4416 (2007).
Yang, M. et al. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 46, 8058–8065 (2007).
Shih, J. C., Chen, K. & Ridd, M. J. Monoamine oxidase: from genes to behavior. Annu. Rev. Neurosci. 22, 197–217 (1999).
Ueda, R. et al. Identification of cell-active lysine specific demethylase 1-selective inhibitors. J. Am. Chem. Soc. 131, 17536–17537 (2009).
Mimasu, S. et al. Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1. Biochemistry 49, 6494–6503 (2010).
Neelamegam, R. et al. Brain-penetrant LSD1 inhibitors can block memory consolidation. ACS Chem. Neurosci. 3, 120–128 (2012).
Maes, T. et al. Preclinical characterization of a potent and selective inhibitor of the histone demethylase KDM1A for MLL leukemia. J. Clin. Oncol. Abstr. 31, e13543 (2013).
Lohse, B. et al. Inhibitors of histone demethylases. Bioorg. Med. Chem. 19, 3625–3636 (2011).
Huang, Y. et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc. Natl Acad. Sci. USA 104, 8023–8028 (2007).
Huang, Y. et al. Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin. Cancer Res. 15, 7217–7228 (2009).
Willmann, D. et al. Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor. Int. J. Cancer 131, 2704–2709 (2012).
Wang, J. et al. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res. 71, 7238–7249 (2011).
Cain, C. AML takes LSD1. SciBx http://dx.doi.org/10.1038/scibx.2012.352 (2012).
Fiskus, W. et al. Pre-clinical efficacy of combined therapy with LSD1 antagonist SP-2509 and pan-histone deacetylase inhibitor against AML blast progenitor cells. Abstract 868. 54th American Society of Hematology Annual Meeting and Exposition [online], (2012).
Yu, V. et al. High-throughput TR-FRET assays for identifying inhibitors of LSD1 and JMJD2C histone lysine demethylases. J. Biomol. Screen 17, 27–38 (2012).
Vannini, A. et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Natl Acad. Sci. USA 101, 15064–15069 (2004).
Rose, N. R. et al. Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. J. Med. Chem. 51, 7053–7056 (2008).
King, O. N. F. et al. Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. PloS ONE 5, e15535 (2010).
Kruidenier, L. et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404–408 (2012). This is the first reported potent and subfamily-selective JMJC demethylase inhibitor.
Liang, Y. et al. Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Sci. Transl. Med. 5, 167ra165 (2013). In this paper, a pan-JMJC demethylase inhibitor is used to block viral infection in cells.
Wang, L. et al. A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. Nature Commun. 4, 2035 (2013). This paper identifies a pan-JMJC demethylase inhibitor with in vivo activity in a cell based high-throughput screening assay.
Brien, G. L. et al. Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation. Nature Struct. Mol. Biol. 19, 1273–1281 (2012).
Suzuki, C. et al. Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer. Mol. Cancer Ther. 6, 542–551 (2007).
Komiya, K. et al. Expression of Mina53, a novel c-Myc target gene, is a favorable prognostic marker in early stage lung cancer. Lung Cancer 69, 232–238 (2010).
Komiya, K. et al. Mina53, a novel c-Myc target gene, is frequently expressed in lung cancers and exerts oncogenic property in NIH/3T3 cells. J. Cancer Res. Clin. Oncol. 136, 465–473 (2010).
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6817–6824 (2001).
You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001).
Hakimi, M.-A. et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci. USA 99, 7420–7425 (2002).
Lee, M. G. et al. Functional interplay between histone demethylase and deacetylase enzymes. Mol. Cell. Biol. 26, 6395–6402 (2006).
Lan, F. et al. Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448, 718–722 (2007).
Singh, M. M. et al. Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. Neuro-Oncol. 13, 894–903 (2011).
Luger, K., Dechassa, M. L. & Tremethick, D. J. New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? Nature Rev. Mol. Cell Biol. 13, 436–447 (2012).
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Stavropoulos, P., Blobel, G. & Hoelz, A. Crystal structure and mechanism of human lysine-specific demethylase-1. Nature Struct. Mol. Biol. 13, 626–632 (2006).
Kong, X. et al. Catalytic mechanism investigation of lysine-specific demethylase 1 (LSD1): a computational study. PloS ONE 6, e25444 (2011).
Yu, T., Higashi, M., Cembran, A., Gao, J. & Truhlar, D. G. Concerted hydrogen atom and electron transfer mechanism for catalysis by lysine-specific demethylase. J. Phys. Chem. B 117, 8422–8429 (2013).
Schulte, J. H. et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 69, 2065–2071 (2009).
Lim, S. et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis 31, 512–520 (2010).
Ciccone, D. N. et al. KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461, 415–418 (2009).
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).
Okada, Y. et al. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 450, 119–123 (2007).
Inagaki, T. et al. Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. Genes Cells 14, 991–1001 (2009).
Tateishi, K. et al. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458, 757–761 (2009).
Liu, Z. et al. Jmjd1a demethylase-regulated histone modification is essential for cAMP-response element modulator-regulated gene expression and spermatogenesis. J. Biol. Chem. 285, 2758–2770 (2010).
Uemura, M. et al. Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer: in vivo identification from hypoxic tumor cells. Clin. Cancer Res. 6, 4636–4646 (2010).
Qi, J. et al. Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell 18, 23–38 (2010).
Guo, X. et al. The expression of histone demethylase JMJD1A in renal cell carcinoma. Neoplasma 58, 153–157 (2011).
Yamada, D. et al. Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: clinical impact on recurrence after hepatic resection. Ann. Surg. Oncol. 19 (Suppl. 3) 355–364 (2011).
Zhang, Q.-J. et al. The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J. Clin. Invest. 121, 2447–2456 (2011).
Patani, N., Jiang, W. G., Newbold, R. F. & Mokbel, K. Histone-modifier gene expression profiles are associated with pathological and clinical outcomes in human breast cancer. Anticancer Res. 31, 4115–4125 (2011).
Pryor, J. G. et al. Microarray comparative genomic hybridization detection of copy number changes in desmoplastic melanoma and malignant peripheral nerve sheath tumor. Am. J. Dermatopathol. 33, 780–785 (2011).
Vinatzer, U. et al. Mucosa-associated lymphoid tissue lymphoma: novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3. Clin. Cancer Res. 14, 6426–6431 (2008).
Iwamori, N., Zhao, M., Meistrich, M. L. & Matzuk, M. M. The testis-enriched histone demethylase, KDM4D, regulates methylation of histone H3 lysine 9 during spermatogenesis in the mouse but is dispensable for fertility. Biol. Reprod. 84, 1225–1234 (2011).
Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nature Immunol. 11, 936–944 (2010).
Agger, K. et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 23, 1171–1176 (2009).
Barradas, M. et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 23, 1177–1182 (2009).
Ciavatta, D. J. et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J. Clin. Invest. 120, 3209–3219 (2010).
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).
Cox, B. J. et al. Phenotypic annotation of the mouse X chromosome. Genome Res. 20, 1154–1164 (2010).
Lee, S. et al. UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev. Cell 22, 25–37 (2012).
Jankowska, A. M. et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 118, 3932–3941 (2011).
Lederer, D. et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am. J. Hum. Genet. 90, 119–124 (2012).
Ishimura, A. et al. Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression. Development 139, 749–759 (2012).
Fukuda, T., Tokunaga, A., Sakamoto, R. & Yoshida, N. Fbxl10/Kdm2b deficiency accelerates neural progenitor cell death and leads to exencephaly. Mol. Cell. Neurosci. 46, 614–624 (2011).
Kottakis, F. et al. FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol. Cell 43, 285–298 (2011).
Sinha, S. et al. Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma. Mol. Cancer 7, 84 (2008).
Ghosh, A. et al. Association of FANCC and PTCH1 with the development of early dysplastic lesions of the head and neck. Ann. Surg. Oncol. 19 (Suppl. 3), 528–538 (2011).
Laumonnier, F. et al. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J. Med. Genet. 42, 780–786 (2005).
Abidi, F. E., Miano, M. G., Murray, J. C. & Schwartz, C. E. A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin. Genet. 72, 19–22 (2007).
Koivisto, A. M. et al. Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin. Genet. 72, 145–149 (2007).
Klose, R. J. et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889–900 (2007).
Vogt, T. et al. Deficiency of a novel retinoblastoma binding protein 2-homolog is a consistent feature of sporadic human melanoma skin cancer. Lab. Invest. 79, 1615–1627 (1999).
van Zutven, L. J. C. M. et al. Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes Chromosomes Cancer 45, 437–446 (2006).
Pointon, J. J. et al. The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis. Genes Immun. 12, 395–398 (2011).
Catchpole, S. et al. PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells. Int. J. Oncol. 38, 1267–1277 (2011).
Abidi, F. E. et al. Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia. J. Med. Genet. 45, 787–793 (2008).
Jensen, L. R. et al. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am. J. Hum. Genet. 76, 227–236 (2005).
Santos, C. et al. A novel mutation in JARID1C gene associated with mental retardation. Eur. J. Hum. Genet. 14, 583–586 (2006).
Tzschach, A. et al. Novel JARID1C/SMCX mutations in patients with X-linked mental retardation. Hum. Mutat. 27, 389 (2006).
Jensen, L. R. et al. A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C. PathoGenetics 3, 2 (2010).
Santos-Rebouças, C. B. et al. A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay. Neurosci. Lett. 498, 67–71 (2011).
Adegbola, A., Gao, H., Sommer, S. & Browning, M. A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD). Am. J. Med. Genet. A 146A, 505–511 (2008).
Perinchery, G. et al. Deletion of Y-chromosome specific genes in human prostate cancer. J. Urol. 163, 1339–1342 (2000).
Takeuchi, T. et al. Jumonji gene is essential for the neurulation and cardiac development of mouse embryos with a C3H/He background. Mechanisms Dev. 86, 29–38 (1999).
Acknowledgements
We thank M. T. Pedersen and S. Kooistra for critical comments on the manuscript. J.H. was supported by a fellowship from the Villum Foundation. Work in the Helin laboratory is supported by the Danish National Research Foundation (grant number DNRF 82), the Danish Cancer Society, the Danish Council for Strategic Research (grant number 12-110503), the Novo Nordisk Foundation, the Lundbeck Foundation, the European Union's Seventh Framework Programme, the European Research Council (grant number 294666_DNAMET) and the Excellence Programme of the University of Copenhagen.
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DATABASES
Glossary
- Next-generation sequencing
-
A collective term for various technologies that allow high-throughput and low-cost sequencing.
- Exome sequencing
-
A cheaper alternative to whole-genome sequencing that allows sequencing of all coding genes.
- Histone demethylases
-
Enzymes that catalyse the demethylation of methyl groups from amino acids in histones. Histone demethylases are often also called lysine demethylases or, in short, KDMs.
- Histone methyltransferases
-
Enzymes that catalyse the methylation of arginine and lysine residues in histones. The more correct terminology for these proteins is protein arginine methyltransferases (PRMTs) and protein lysine methyltransferases (PKMTs).
- H3K36me3
-
A short notation for the methylation status of trimethylated lysine 36 on histone H3. This notation style is used to describe the methylation states of specific residues in a histone tail.
- Protein domains
-
Parts of a protein with a conserved sequence that can evolve and sometimes function and exist independently of the rest of the protein.
- Catalytic domain
-
The part of the enzyme where the reaction of the substrate occurs.
- Inhibitor
-
A molecule that blocks the activity of a target protein.
- Potency
-
A measure of drug activity that is defined as the amount of a compound required to elicit an effect of a given strength.
- Target selectivity
-
The degree to which a drug can affect a target protein without affecting other proteins. This is an attribute that is difficult to obtain when proteins that are similar to the target protein exist.
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Højfeldt, J., Agger, K. & Helin, K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov 12, 917–930 (2013). https://doi.org/10.1038/nrd4154
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DOI: https://doi.org/10.1038/nrd4154
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