Abstract
Renal cell carcinomas (RCCs) are a diverse set of malignancies that have recently been shown to harbour mutations in a number of chromatin modifier genes — including PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2 — through high-throughput sequencing efforts. Current research focuses on understanding the biological activities that chromatin modifiers employ to suppress tumorigenesis and on developing clinical approaches that take advantage of this knowledge. Unsurprisingly, several common themes unify the functions of these epigenetic modifiers, particularly regulation of histone post-translational modifications and nucleosome organization. Furthermore, chromatin modifiers also govern processes crucial for DNA repair and maintenance of genomic integrity as well as the regulation of splicing and other key processes. Many chromatin modifiers have additional non-canonical roles in cytoskeletal regulation, which further contribute to genomic stability, expanding the repertoire of functions that might be essential in tumorigenesis. Our understanding of how mutations in chromatin modifiers contribute to tumorigenesis in RCC is improving but remains an area of intense investigation. Importantly, elucidating the activities of chromatin modifiers offers intriguing opportunities for the development of new therapeutic interventions in RCC.
Key points
-
Loss-of-function mutations in chromatin modifiers, which are common in renal cell carcinoma (RCC), can modify tumour biology and influence therapeutic responses; thus, understanding how these events contribute to RCC is paramount.
-
Chromatin modifiers classically regulate genomic architecture and, therefore, control DNA accessibility; these canonical functions are fundamental for essential cellular processes, such as gene expression programmes and DNA damage repair.
-
Chromatin modifiers have non-histone substrates and participate in extranuclear processes; these non-canonical functions regulate important cellular processes, such as cytoskeletal dynamics and immune responses.
-
Loss-of-function mutations in chromatin modifiers can be approached therapeutically by exploiting synthetically lethal dependencies between two genes; loss of both genes induces cell death, but loss of either is nonfatal.
This is a preview of subscription content, access via your institution
Access options
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
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
American Cancer Society. Cancer facts & figures 2018. Cancer.org https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf (2018).
Miller, D. C. et al. Contemporary clinical epidemiology of renal cell carcinoma: insight from a population based case-control study. J. Urol. 184, 2254–2258 (2010).
Graham, J. & Heng, D. Y. Real-world evidence in metastatic renal cell carcinoma. Tumori https://doi.org/10.1177/0300891618761004 (2018).
Heng, D. Y. et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J. Clin. Oncol. 27, 5794–5799 (2009).
Nabi, S., Kessler, E. R., Bernard, B., Flaig, T. W. & Lam, E. T. Renal cell carcinoma: a review of biology and pathophysiology. F1000Res. 7, 307 (2018).
Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45, 860–867 (2013).
Cancer Genome Atlas Research Network et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016).
Maher, E. R. & Kaelin, W. G. Jr. von Hippel-Lindau disease. Medicine (Baltimore) 76, 381–391 (1997).
Ricketts, C. J. et al. The Cancer Genome Atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 23, 313–326.e5 (2018).
Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal. Cell 173, 611–623.e17 (2018).
Turajlic, S. et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx Renal. Cell 173, 595–610.e11 (2018).
Chen, F. et al. Multilevel genomics-based taxonomy of renal cell carcinoma. Cell Rep. 14, 2476–2489 (2016).
Bratslavsky, G., Sudarshan, S., Neckers, L. & Linehan, W. M. Pseudohypoxic pathways in renal cell carcinoma. Clin. Cancer Res. 13, 4667–4671 (2007).
Nielsen, O. H., Grimm, D., Wehland, M., Bauer, J. & Magnusson, N. E. Anti-angiogenic drugs in the treatment of metastatic renal cell carcinoma: advances in clinical application. Curr. Vasc. Pharmacol. 13, 381–391 (2015).
Kaelin, W. G. Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat. Rev. Cancer 8, 865–873 (2008).
Simon, J. M. et al. Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Genome Res. 24, 241–250 (2014).
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
Guo, G. et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat. Genet. 44, 17–19 (2011).
Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).
Biegel, J. A., Busse, T. M. & Weissman, B. E. SWI/SNF chromatin remodeling complexes and cancer. Am. J. Med. Genet. C. Semin. Med. Genet. 166C, 350–366 (2014).
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Davis, C. F. et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26, 319–330 (2014).
Hauer, M. H. & Gasser, S. M. Chromatin and nucleosome dynamics in DNA damage and repair. Genes Dev. 31, 2204–2221 (2017).
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).
Conaway, R. C. & Conaway, J. W. The INO80 chromatin remodeling complex in transcription, replication and repair. Trends Biochem. Sci. 34, 71–77 (2009).
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).
Li, M. et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. 43, 828–829 (2011).
Wang, K. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 43, 1219–1223 (2011).
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).
Reisman, D., Glaros, S. & Thompson, E. A. The SWI/SNF complex and cancer. Oncogene 28, 1653–1668 (2009).
Nie, Z. et al. A specificity and targeting subunit of a human SWI/SNF family-related chromatin-remodeling complex. Mol. Cell. Biol. 20, 8879–8888 (2000).
Wang, X. et al. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem. J. 383, 319–325 (2004).
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).
Kaeser, M. D. et al. BRD7, a novel PBAF-specific SWI/SNF subunit, is required for target gene activation and repression in embryonic stem cells. J. Biol. Chem. 283, 32254–32263 (2008).
Wang, Z. et al. Polybromo protein BAF180 functions in mammalian cardiac chamber maturation. Genes Dev. 18, 3106–3116 (2004).
Brownlee, P. M., Chambers, A. L., Oliver, A. W. & Downs, J. A. Cancer and the bromodomains of BAF180. Biochem. Soc. Trans. 40, 364–369 (2012).
Thompson, M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009).
Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).
Forbes, S. A. et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 45, D777–D783 (2017).
COSMIC. Catalogue of somatic mutations in cancer. Sanger http://cancer.sanger.ac.uk (2017).
Turajlic, S., Larkin, J. & Swanton, C. SnapShot: renal cell carcinoma. Cell 163, 1556–1556.e1 (2015).
Rao, Q. et al. Coexistent loss of INI1 and BRG1 expression in a rhabdoid renal cell carcinoma (RCC): implications for a possible role of SWI/SNF complex in the pathogenesis of RCC. Int. J. Clin. Exp. Pathol. 7, 1782–1787 (2014).
Kapur, P. et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 14, 159–167 (2013).
Murakami, A. et al. Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma. Oncogenesis 6, e287 (2017).
Gao, W., Li, W., Xiao, T., Liu, X. S. & Kaelin, W. G. Jr. Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/− clear cell renal carcinoma. Proc. Natl Acad. Sci. USA 114, 1027–1032 (2017).
Nargund, A. M. et al. The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma. Cell Rep. 18, 2893–2906 (2017).
Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).
Shu, X. S. et al. The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer. J. Pathol. 244, 36–48 (2018).
Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).
Jensen, D. E. et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097–1112 (1998).
Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).
Lee, H. S., Lee, S. A., Hur, S. K., Seo, J. W. & Kwon, J. Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis. Nat. Commun. 5, 5128 (2014).
Scheuermann, J. C. et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465, 243–247 (2010).
Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).
Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).
Bernstein, E. et al. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol. Cell. Biol. 26, 2560–2569 (2006).
Tavares, L. et al. RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 148, 664–678 (2012).
van den Boom, V. et al. Non-canonical PRC1.1 targets active genes independent of H3K27me3 and is essential for leukemogenesis. Cell Rep. 14, 332–346 (2016).
Farcas, A. M. et al. KDM2B links the polycomb repressive complex 1 (PRC1) to recognition of CpG islands. eLife 1, e00205 (2012).
Blackledge, N. P. et al. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell 157, 1445–1459 (2014).
Edmunds, J. W., Mahadevan, L. C. & Clayton, A. L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27, 406–420 (2008).
Strahl, B. D. et al. Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol. Cell. Biol. 22, 1298–1306 (2002).
Li, M. et al. Solution structure of the Set2-Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1. Proc. Natl Acad. Sci. USA 102, 17636–17641 (2005).
Kobor, M. S. & Greenblatt, J. Regulation of transcription elongation by phosphorylation. Biochim. Biophys. Acta 1577, 261–275 (2002).
Niu, X. et al. The von Hippel-Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C. Oncogene 31, 776–786 (2012).
Rondinelli, B. et al. Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. J. Clin. Invest. 125, 4625–4637 (2015).
Pena-Llopis, S., Christie, A., Xie, X. J. & Brugarolas, J. Cooperation and antagonism among cancer genes: the renal cancer paradigm. Cancer Res. 73, 4173–4179 (2013).
Hakimi, A. A. et al. Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. Eur. Urol. 63, 848–854 (2013).
Gossage, L. et al. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes Chromosomes Cancer 53, 38–51 (2014).
Liu, L. et al. Loss of SETD2, but not H3K36me3, correlates with aggressive clinicopathological features of clear cell renal cell carcinoma patients. Biosci. Trends 11, 214–220 (2017).
Pawlowski, R. et al. Loss of PBRM1 expression is associated with renal cell carcinoma progression. Int. J. Cancer 132, E11–E17 (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).
da Costa, W. H. et al. Prognostic impact of concomitant loss of PBRM1 and BAP1 protein expression in early stages of clear cell renal cell carcinoma. Urol. Oncol. 36, 243.e1–243.e8 (2018).
Martinez, P. et al. Parallel evolution of tumour subclones mimics diversity between tumours. J. Pathol. 230, 356–364 (2013).
Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014).
Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx Renal. Cell 173, 581–594.e12 (2018).
Ricketts, C. J. & Linehan, W. M. Multi-regional sequencing elucidates the evolution of clear cell renal cell carcinoma. Cell 173, 540–542 (2018).
Mandriota, S. J. et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1, 459–468 (2002).
Frew, I. J. et al. pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J. 27, 1747–1757 (2008).
Rankin, E. B., Tomaszewski, J. E. & Haase, V. H. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res. 66, 2576–2583 (2006).
Dey, A. et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337, 1541–1546 (2012).
Hu, M. et al. Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proc. Natl Acad. Sci. USA 107, 2956–2961 (2010).
Huang, X., Gao, X., Diaz-Trelles, R., Ruiz-Lozano, P. & Wang, Z. Coronary development is regulated by ATP-dependent SWI/SNF chromatin remodeling component BAF180. Dev. Biol. 319, 258–266 (2008).
Gu, Y. F. et al. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov. 7, 900–917 (2017).
Wang, S. S. et al. Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proc. Natl Acad. Sci. USA 111, 16538–16543 (2014).
Kovac, M. et al. Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. Nat. Commun. 6, 6336 (2015).
Ho, T. H. et al. Loss of PBRM1 and BAP1 expression is less common in non-clear cell renal cell carcinoma than in clear cell renal cell carcinoma. Urol. Oncol. 33, 23.e9–23.e14 (2015).
Malouf, G. G. et al. Genomic characterization of renal cell carcinoma with sarcomatoid dedifferentiation pinpoints recurrent genomic alterations. Eur. Urol. 70, 348–357 (2016).
Wang, Z. et al. Sarcomatoid renal cell carcinoma has a distinct molecular pathogenesis, driver mutation profile, and transcriptional landscape. Clin. Cancer Res. 23, 6686–6696 (2017).
Dietlein, F., Thelen, L. & Reinhardt, H. C. Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genet. 30, 326–339 (2014).
Chapman, J. R., Taylor, M. R. & Boulton, S. J. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell 47, 497–510 (2012).
Risinger, J. I., Barrett, J. C., Watson, P., Lynch, H. T. & Boyd, J. Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer 77, 1836–1843 (1996).
Li, F. et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha. Cell 153, 590–600 (2013).
Acharya, S. et al. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc. Natl Acad. Sci. USA 93, 13629–13634 (1996).
Laguri, C. et al. Human mismatch repair protein MSH6 contains a PWWP domain that targets double stranded DNA. Biochemistry 47, 6199–6207 (2008).
Musselman, C. A. et al. Molecular basis for H3K36me3 recognition by the Tudor domain of PHF1. Nat. Struct. Mol. Biol. 19, 1266–1272 (2012).
Hayakawa, T. et al. MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. J. Cell Sci. 123, 1124–1130 (2010).
Daugaard, M. et al. LEDGF (p75) promotes DNA-end resection and homologous recombination. Nat. Struct. Mol. Biol. 19, 803–810 (2012).
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).
Li, L. & Wang, Y. Crosstalk between the H3K36me3 and H4K16ac histone epigenetic marks in DNA double-strand break repair. J. Biol. Chem. 292, 11951–11959 (2017).
Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).
Pai, C. C. et al. A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice. Nat. Commun. 5, 4091 (2014).
Palii, S. S., Cui, Y., Innes, C. L. & Paules, R. S. Dissecting cellular responses to irradiation via targeted disruptions of the ATM-CHK1-PP2A circuit. Cell Cycle 12, 1105–1118 (2013).
Feng, C. et al. PI3Kbeta inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways. Sci. Rep. 5, 9465 (2015).
Hacker, K. E. et al. Structure/function analysis of recurrent mutations in SETD2 protein reveals a critical and conserved role for a SET domain residue in maintaining protein stability and histone H3 Lys-36 trimethylation. J. Biol. Chem. 291, 21283–21295 (2016).
Kanu, N. et al. SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene 34, 5699–5708 (2015).
Sveen, A., Kilpinen, S., Ruusulehto, A., Lothe, R. A. & Skotheim, R. I. Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene 35, 2413–2427 (2016).
Kolasinska-Zwierz, P. et al. Differential chromatin marking of introns and expressed exons by H3K36me3. Nat. Genet. 41, 376–381 (2009).
de Almeida, S. F. et al. Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Nat. Struct. Mol. Biol. 18, 977–983 (2011).
Convertini, P. et al. Sudemycin E influences alternative splicing and changes chromatin modifications. Nucleic Acids Res. 42, 4947–4961 (2014).
Sanidas, I. et al. Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer. Mol. Cell 53, 577–590 (2014).
Xie, L. et al. KDM5B regulates embryonic stem cell self-renewal and represses cryptic intragenic transcription. EMBO J. 30, 1473–1484 (2011).
Guo, R. et al. BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol. Cell 56, 298–310 (2014).
Chowdhury, B. et al. PBRM1 regulates the expression of genes involved in metabolism and cell adhesion in renal clear cell carcinoma. PLoS ONE 11, e0153718 (2016).
Kenneth, N. S., Mudie, S., van Uden, P. & Rocha, S. SWI/SNF regulates the cellular response to hypoxia. J. Biol. Chem. 284, 4123–4131 (2009).
Schmitges, F. W. et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Mol. Cell 42, 330–341 (2011).
Brien, G. L. et al. Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation. Nat. Struct. Mol. Biol. 19, 1273–1281 (2012).
Ballare, C. et al. Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity. Nat. Struct. Mol. Biol. 19, 1257–1265 (2012).
Cai, L. et al. An H3K36 methylation-engaging Tudor motif of polycomb-like proteins mediates PRC2 complex targeting. Mol. Cell 49, 571–582 (2013).
Ferrari, K. J. et al. Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Mol. Cell 53, 49–62 (2014).
Goll, M. G. & Bestor, T. H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).
Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243–247 (2015).
Hahn, M. A., Wu, X., Li, A. X., Hahn, T. & Pfeifer, G. P. Relationship between gene body DNA methylation and intragenic H3K9me3 and H3K36me3 chromatin marks. PLoS ONE 6, e18844 (2011).
Manzo, M. et al. Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands. EMBO J. 36, 3421–3434 (2017).
Hogart, A. et al. Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites. Genome Res. 22, 1407–1418 (2012).
Clark, S. J., Harrison, J. & Molloy, P. L. Sp1 binding is inhibited by (m)Cp(m)CpG methylation. Gene 195, 67–71 (1997).
Tiedemann, R. L. et al. Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. Oncotarget 7, 1927–1946 (2016).
Su, X. et al. NSD1 inactivation and SETD2 mutation drive a convergence toward loss of function of H3K36 writers in clear cell renal cell carcinomas. Cancer Res. 77, 4835–4845 (2017).
Park, I. Y. et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166, 950–962 (2016).
Chen, K. et al. Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell 170, 492–506.e14 (2017).
Chiang, Y. C. et al. SETD2 haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-17-3460 (2018).
Mashtalir, N. et al. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol. Cell 54, 392–406 (2014).
Bononi, A. et al. Germline BAP1 mutations induce a Warburg effect. Cell Death Differ. 24, 1694–1704 (2017).
Dai, F. et al. BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response. Proc. Natl Acad. Sci. USA 114, 3192–3197 (2017).
Baughman, J. M. et al. NeuCode proteomics reveals Bap1 regulation of metabolism. Cell Rep. 16, 583–595 (2016).
Hebert, L. et al. Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function. Oncotarget 8, 72513–72527 (2017).
Luchini, C. et al. Different prognostic roles of tumor suppressor gene BAP1 in cancer: a systematic review with meta-analysis. Genes Chromosomes Cancer 55, 741–749 (2016).
Palmer, A. E., Jin, C., Reed, J. C. & Tsien, R. Y. Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc. Natl Acad. Sci. USA 101, 17404–17409 (2004).
Bononi, A. et al. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546, 549–553 (2017).
Verhey, K. J. & Gaertig, J. The tubulin code. Cell Cycle 6, 2152–2160 (2007).
Zarrizi, R., Menard, J. A., Belting, M. & Massoumi, R. Deubiquitination of gamma-tubulin by BAP1 prevents chromosome instability in breast cancer cells. Cancer Res. 74, 6499–6508 (2014).
Kollman, J. M., Merdes, A., Mourey, L. & Agard, D. A. Microtubule nucleation by gamma-tubulin complexes. Nat. Rev. Mol. Cell Biol. 12, 709–721 (2011).
Sankaran, S., Starita, L. M., Groen, A. C., Ko, M. J. & Parvin, J. D. Centrosomal microtubule nucleation activity is inhibited by BRCA1-dependent ubiquitination. Mol. Cell. Biol. 25, 8656–8668 (2005).
Hsu, C. C. et al. 58-kDa microspherule protein (MSP58) is novel Brahma-related gene 1 (BRG1)-associated protein that modulates p53/p21 senescence pathway. J. Biol. Chem. 287, 22533–22548 (2012).
Peng, J. et al. Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma. Cancer Lett. 369, 167–174 (2015).
Cui, K. et al. The chromatin-remodeling BAF complex mediates cellular antiviral activities by promoter priming. Mol. Cell. Biol. 24, 4476–4486 (2004).
Wang, H. et al. PBRM1 regulates proliferation and the cell cycle in renal cell carcinoma through a chemokine/chemokine receptor interaction pathway. PLOS One 12, e0180862 (2017).
He, X. et al. Bap180/Baf180 is required to maintain homeostasis of intestinal innate immune response in Drosophila and mice. Nat. Microbiol. 2, 17056 (2017).
Pfister, S. X. et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28, 557–568 (2015).
Bucher, N. & Britten, C. D. G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. Br. J. Cancer 98, 523–528 (2008).
Beck, H. et al. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol. Cell. Biol. 32, 4226–4236 (2012).
Wang, J. et al. High selectivity of PI3Kbeta inhibitors in SETD2-mutated renal clear cell carcinoma. J. BUON 20, 1267–1275 (2015).
Feng, C., Ding, G., Jiang, H., Ding, Q. & Wen, H. Loss of MLH1 confers resistance to PI3Kbeta inhibitors in renal clear cell carcinoma with SETD2 mutation. Tumour Biol. 36, 3457–3464 (2015).
LaFave, L. M. et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat. Med. 21, 1344–1349 (2015).
Schoumacher, M. et al. Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status. Nat. Med. 22, 577–578 (2016).
LaFave, L. M. et al. Reply to “Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status”. Nat. Med. 22, 578–579 (2016).
Kim, K. H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (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).
Bitler, B. G. et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231–238 (2015).
Hopkins, S. R., McGregor, G. A., Murray, J. M., Downs, J. A. & Savic, V. Novel synthetic lethality screening method identifies TIP60-dependent radiation sensitivity in the absence of BAF180. DNA Repair (Amst.) 46, 47–54 (2016).
Samartzis, E. P. et al. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget 5, 5295–5303 (2014).
Shen, J. et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 5, 752–767 (2015).
Konings, I. R., Verweij, J., Wiemer, E. A. & Sleijfer, S. The applicability of mTOR inhibition in solid tumors. Curr. Cancer Drug Targets 9, 439–450 (2009).
Zhang, N. & Bevan, M. J. CD8+ T cells: foot soldiers of the immune system. Immunity 35, 161–168 (2011).
Acknowledgements
The authors acknowledge the support of the NIH: grants R01CA198482 (W.K.R.), K24CA172355 (W.K.R.), and T32CA009582 (A.A.d.C.). This work was performed in part at the Aspen Center for Physics, which is supported by National Science Foundation grant PHY-1607611.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to this manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Clear cell renal cell carcinoma
-
(ccRCC). The most common histological subtype of RCC, originating from cells of the proximal convoluted tubule.
- Chromophobe renal cell carcinoma
-
(chRCC). A rare variant of RCC that is frequently characterized by mutations in PTEN and TP53 as well as the loss of chromosomes 1, 2, 6, 10, 13, 17, and 21.
- Renal medullary carcinoma
-
A very rare renal cell carcinoma histology that occurs almost exclusively in young people of African-American descent.
- Post-translational modifications
-
(PTMs). The covalent, and generally enzymatic, modification of proteins following protein biosynthesis.
- Ubiquitylation
-
The process by which ubiquitin is covalently attached to substrate proteins.
- Multi-region genomic profiling
-
Refers to a genomic analysis involving multiple samples derived from a single tumour specimen.
- Type 1 pRCC
-
A histological subtype of papillary renal cell carcinoma (pRCC) that generally comprises indolent tumours and is characterized by activating mutations in the MET oncogene and gains in chromosome 3, 7, and 17.
- Type 2 pRCC
-
A histological subtype of papillary renal cell carcinoma (pRCC) that generally comprises aggressive tumours and can harbour mutations in the FH gene.
- Renal oncocytomas
-
Benign renal tumours.
- Sarcomatoid RCCs
-
Refers to renal cell carcinoma (RCC) tumours that display sarcomatoid (or spindle-shaped cell) morphology. These variants of the conventional histological subtypes clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC) are typically more aggressive and rapidly lethal than non-sarcomatoid variants.
- DNA mismatch repair
-
(DNA MMR). A genomic maintenance system by which misincorporated nucleotides and insertion–deletion mispairings are removed and corrected in newly synthesized DNA.
- Double-strand break repair
-
(DSB repair). DSBs can result from genotoxic insults, where both strands of DNA are broken as a result; if not properly repaired, DNA DSBs can result in genomic rearrangements or cell death. DSBs can be resolved either by homologous recombination or non-homologous end joining.
- Homologous recombination
-
(HR). Refers to the DNA repair pathway that is most widely used by cells to accurately repair DNA double-strand breaks, whereby nucleotide sequences are exchanged between two similar or identical DNA molecules.
- Non-homologous end joining
-
(NHEJ). A DNA repair pathway whereby the ends of the DNA break are directly ligated without the need for a homologous template.
- Euchromatin
-
Refers to chromatin that is in a relaxed state and is associated with active transcription.
- Cryptic transcription
-
An aberrant process by which polymerase initiates transcription at a location other than canonical promoters, such as in the gene body.
- Nonsense-mediated decay pathway
-
(NMD pathway). A surveillance pathway that exists in all eukaryotes and primarily functions to reduce erroneous gene expression by eliminating mRNA transcripts that contain premature stop codons.
- CpG island methylator phenotype
-
(CIMP). Refers to global genome hypermethylation that is thought to promote tumorigenesis by switching off tumour suppressor genes.
- Differentially methylated regions
-
(DMRs). Genomic regions with a different DNA methylation status among a group of samples (for example, among tissues or individuals) that are regarded as possible functional regions involved in transcriptional regulation.
- Micronuclei
-
Extranuclear bodies that contain fragments of chromosomes, resulting from erroneous cell division.
Rights and permissions
About this article
Cite this article
de Cubas, A.A., Rathmell, W.K. Epigenetic modifiers: activities in renal cell carcinoma. Nat Rev Urol 15, 599–614 (2018). https://doi.org/10.1038/s41585-018-0052-7
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41585-018-0052-7
This article is cited by
-
ADAMTS9-AS1 inhibits tumor growth and drug resistance in clear cell renal cell carcinoma via recruiting HuR to enhance ADAMTS9 mRNA stability
Cancer Nanotechnology (2023)
-
PBRM1, SETD2 and BAP1 — the trinity of 3p in clear cell renal cell carcinoma
Nature Reviews Urology (2023)
-
SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
Nature Communications (2023)
-
Identification of molecular subtypes based on chromatin regulator and tumor microenvironment infiltration characterization in papillary renal cell carcinoma
Journal of Cancer Research and Clinical Oncology (2023)
-
Molecular differences in renal cell carcinoma between males and females
World Journal of Urology (2023)