The Emerging Role of Histone Demethylases in Renal Cell Carcinoma

Main Article Content

Xiaoqiang Guo
Qiaoxia Zhang

Keywords

histone demethylases, KDM3A, KDM5C, KDM6A, KDM6B, renal cell carcinoma

Abstract

Renal cell carcinoma (RCC), the most common kidney cancer, is responsible for more than 100,000 deaths per year worldwide. The molecular mechanism of RCC is poorly understood. Many studies have indicated that epigenetic changes such as DNA methylation, noncoding RNAs, and histone modifications are central to the pathogenesis of cancer. Histone demethylases (KDMs) play a central role in histone modifications. There is emerging evidence that KDMs such as KDM3A, KDM5C, KDM6A, and KDM6B play important roles in RCC. The available literature suggests that KDMs could promote RCC development and progression via hypoxia-mediated angiogenesis pathways. Small-molecule inhibitors of KDMs are being developed and used in preclinical studies; however, their clinical relevance is yet to be established. In this mini review, we summarize our current knowledge on the putative role of histone demethylases in RCC.

Abstract 3134 | PDF Downloads 1454 HTML Downloads 1818 XML Downloads 628

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. http://dx.doi.org/10.3322/caac.21254
2. Ficarra V, Schips L, Guille F, Li G, De La Taille A, Prayer Galetti T, et al. Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma. Cancer. 2005;104(5):968–74. http://dx.doi.org/10.1002/cncr.21254
3. Mohammed A, Shergill I, Little B. Management of metastatic renal cell carcinoma: Current trends. Expert Rev Mol Diagn. 2009;9(1):75–83. http://dx.doi.org/10.1586/14737159.9.1.75
4. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28. http://dx.doi.org/10.1038/nrg816
5. Tessarz P, Kouzarides T. Histone core modifications regulating nucleosome structure and dynamics. Nat Rev Mol Cell Biol. 2014;15(11):703–8. http://dx.doi.org/10.1038/nrm3890
6. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95. http://dx.doi.org/10.1038/cr.2011.22
7. Greer EL, Shi Y. Histone methylation: A dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13(5):343–57. http://dx.doi.org/10.1038/nrg3173
8. Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: Establishment, regulation, and biological impact. Mol Cell. 2012;48(4):491–507. http://dx.doi.org/10.1016/j.molcel.2012.11.006
9. Pedersen MT, Helin K. Histone demethylases in development and disease. Trends Cell Biol. 2010;20(11):662–71. http://dx.doi.org/10.1016/j.tcb.2010.08.011
10. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941–53. http://dx.doi.org/10.1016/j.cell.2004.12.012
11. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006;439(7078):811–16. http://dx.doi.org/10.1038/nature04433
12. Dimitrova E, Turberfield AH, Klose RJ. Histone demethylases in chromatin biology and beyond. EMBO Rep. 2015;16(12):1620–39. http://dx.doi.org/10.15252/embr.201541113
13. Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature. 2007;450(7166):119–23. http://dx.doi.org/10.1038/nature06236
14. Tateishi K, Okada Y, Kallin EM, Zhang Y. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature. 2009;458(7239):757–61. http://dx.doi.org/10.1038/nature07777
15. Kasioulis I, Syred HM, Tate P, Finch A, Shaw J, Seawright A, et al. Kdm3a lysine demethylase is an Hsp90 client required for cytoskeletal rearrangements during spermatogenesis. Mol Biol Cell. 2014;25(8):1216–33. http://dx.doi.org/10.1091/mbc.E13-08-0471
16. Yamada D, Kobayashi S, Yamamoto H, Tomimaru Y, Noda T, Uemura M, et al. Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: Clinical impact on recurrence after hepatic resection. Ann Surg Oncol. 2012;19 Suppl 3:S355–64. http://dx.doi.org/10.1245/s10434-011-1797-x
17. Yang H, Liu Z, Yuan C, Zhao Y, Wang L, Hu J, et al. Elevated JMJD1A is a novel predictor for prognosis and a potential therapeutic target for gastric cancer. Int J Clin Exp Pathol. 2015;8(9):11092–9.
18. Guo X, Shi M, Sun L, Wang Y, Gui Y, Cai Z, et al. The expression of histone demethylase JMJD1A in renal cell carcinoma. Neoplasma. 2011;58(2):153–7. http://dx.doi.org/10.4149/neo_2011_02_153
19. Krieg AJ, Rankin EB, Chan D, Razorenova O, Fernandez S, Giaccia AJ. Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth. Mol Cell Biol. 2010;30(1):344–53. http://dx.doi.org/10.1128/MCB.00444-09
20. Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010;463(7279):360–3. http://dx.doi.org/10.1038/nature08672
21. Gossage L, Murtaza M, Slatter AF, Lichtenstein CP, Warren A, Haynes B, et al. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes Chromosomes Cancer. 2014;53(1):38–51. http://dx.doi.org/10.1002/gcc.22116
22. Shen Y, Guo X, Wang Y, Qiu W, Chang Y, Zhang A, et al. Expression and significance of histone H3K27 demethylases in renal cell carcinoma. BMC Cancer. 2012;12:470. http://dx.doi.org/10.1186/1471-2407-12-470
23. Kramer JM, van Bokhoven H. Genetic and epigenetic defects in mental retardation. Int J Biochem Cell Biol. 2009;41(1):96–107. http://dx.doi.org/10.1016/j.biocel.2008.08.009
24. Wang Q, Wei J, Su P, Gao P. Histone demethylase JARID1C promotes breast cancer metastasis cells via down regulating BRMS1 expression. Biochem Biophys Res Commun. 2015;464(2):659–66. http://dx.doi.org/10.1016/j.bbrc.2015.07.049
25. Van der Meulen J, Speleman F, Van Vlierberghe P. The H3K27me3 demethylase UTX in normal development and disease. Epigenetics. 2014;9(5):658–68. http://dx.doi.org/10.4161/epi.28298
26. van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 2009;41(5):521–3. http://dx.doi.org/10.1038/ng.349
27. Swigut T, Wysocka J. H3K27 demethylases, at long last. Cell. 2007;131(1):29–32. http://dx.doi.org/10.1016/j.cell.2007.09.026
28. Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruïne AP. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221(2):125–38. http://dx.doi.org/10.1002/path.2689
29. Hancock RL, Dunne K, Walport LJ, Flashman E, Kawamura A. Epigenetic regulation by histone demethylases in hypoxia. Epigenomics. 2015;7(5):791–811. http://dx.doi.org/10.2217/epi.15.24
30. Xia X, Lemieux ME, Li W, Carroll JS, Brown M, Liu XS, et al. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci USA. 2009;106(11):4260–5. http://dx.doi.org/10.1073/pnas.0810067106
31. Melvin A, Rocha S. Chromatin as an oxygen sensor and active player in the hypoxia response. Cell Signal. 2012;24(1):35–43. http://dx.doi.org/10.1016/j.cellsig.2011.08.019
32. Beyer S, Kristensen MM, Jensen KS, Johansen JV, Staller P. The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. J Biol Chem. 2008;283(52):36542–52. http://dx.doi.org/10.1074/jbc.M804578200
33. Wellmann S, Bettkober M, Zelmer A, Seeger K, Faigle M, Eltzschig HK, et al. Hypoxia upregulates the histone demethylase JMJD1A via HIF-1. Biochem Biophys Res Commun. 2008;372(4):892–7. http://dx.doi.org/10.1016/j.bbrc.2008.05.150
34. Sar A, Ponjevic D, Nguyen M, Box AH, Demetrick DJ. Identification and characterization of demethylase JMJD1A as a gene upregulated in the human cellular response to hypoxia. Cell Tissue Res. 2009;337(2):223–34. http://dx.doi.org/10.1007/s00441-009-0805-y
35. Pollard PJ, Loenarz C, Mole DR, McDonough MA, Gleadle JM, Schofield CJ, et al. Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. Biochem J. 2008;416(3):387–94. http://dx.doi.org/10.1042/BJ20081238
36. Lee HY, Choi K, Oh H, Park YK, Park H. HIF-1-dependent induction of Jumonji domain-containing protein (JMJD) 3 under hypoxic conditions. Mol Cells. 2014;37(1):43–50. http://dx.doi.org/10.14348/molcells.2014.2250
37. Guo X, Tian Z, Wang X, Pan S, Huang W, Shen Y, et al. Regulation of histone demethylase KDM6B by hypoxia-inducible factor-2α. Acta Biochim Biophys Sin (Shanghai). 2015;47(2):106–13. http://dx.doi.org/10.1093/abbs/gmu122
38. Guo X, Li X, Wang Y, Tian Z, Duan X, Cai Z. Nicotine induces alteration of H3K27 demethylase UTX in kidney cancer cell. Hum Exp Toxicol. 2014;33(3):264–9. http://dx.doi.org/10.1177/0960327113499043
39. Guo X, Zhang Y, Zhang Q, Fa P, Gui Y, Gao G, et al. The regulatory role of nickel on H3K27 demethylase JMJD3 in kidney cancer cells. Toxicol Ind Health. 2016;32(7):1286–92. http://dx.doi.org/10.1177/0748233714552687
40. Lipworth L, Tarone RE, McLaughlin JK. The epidemiology of renal cell carcinoma. J Urol. 2006;176(6 Pt 1):2353–8. http://dx.doi.org/10.1016/j.juro.2006.07.130
41. Mimura I, Nangaku M, Kanki Y, Tsutsumi S, Inoue T, Kohro T, et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol. 2012;32(15):3018–32. http://dx.doi.org/10.1128/MCB.06643-11
42. Park SJ, Kim JG, Son TG, Yi JM, Kim ND, Yang K, et al. The histone demethylase JMJD1A regulates adrenomedullin-mediated cell proliferation in hepatocellular carcinoma under hypoxia. Biochem Biophys Res Commun. 2013;434(4):722–7. http://dx.doi.org/10.1016/j.bbrc.2013.03.091
43. Osawa T, Tsuchida R, Muramatsu M, Shimamura T, Wang F, Suehiro J, et al. Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages. Cancer Res. 2013;73(10):3019–28. http://dx.doi.org/10.1158/0008-5472.CAN-12-3231
44. Niu X, Zhang T, Liao L, Zhou L, Lindner DJ, Zhou M, et al. The von Hippel-Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C. Oncogene. 2012;31(6):776–86. http://dx.doi.org/10.1038/onc.2011.266
45. Rondinelli B, Rosano D, Antonini E, Frenquelli M, Montanini L, Huang D, et al. Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. J Clin Invest. 2015;125(12):4625–37. http://dx.doi.org/10.1172/JCI81040
46. Su D, Stamatakis L, Singer EA, Srinivasan R. Renal cell carcinoma: Molecular biology and targeted therapy. Curr Opin Oncol. 2014;26(3):321–7. http://dx.doi.org/10.1097/CCO.0000000000000069
47. Natoli G, Testa G, De Santa F. The future therapeutic potential of histone demethylases: A critical analysis. Curr Opin Drug Discov Devel. 2009;12(5):607–15.
48. McAllister TE, England KS, Hopkinson RJ, Brennan PE, Kawamura A, Schofield CJ. Recent progress in histone demethylase inhibitors. J Med Chem. 2016;59(4):1308–29. http://dx.doi.org/10.1021/acs.jmedchem.5b01758
49. Gale M, Yan Q. High-throughput screening to identify inhibitors of lysine demethylases. Epigenomics. 2015;7(1):57–65. http://dx.doi.org/10.2217/epi.14.63
50. Rotili D, Tomassi S, Conte M, Benedetti R, Tortorici M, Ciossani G, et al. Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high anticancer activities. J Med Chem. 2014;57(1):42–55. http://dx.doi.org/10.1021/jm4012802
51. Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med. 2014;20(12):1394–6. http://dx.oi.org/10.1038/nm.3716
52. Thinnes CC, England KS, Kawamura A, Chowdhury R, Schofield CJ, Hopkinson RJ. Targeting histone lysine demethylases – Progress, challenges, and the future. Biochim Biophys Acta. 2014;1839(12):1416–32. http://dx.doi.org/10.1016/j.bbagrm.2014.05.009
53. Mund C, Lyko F. Epigenetic cancer therapy: Proof of concept and remaining challenges. Bioessays. 2010;32(11):949–57. http://dx.doi.org/10.1002/bies.201000061
54. Guo X, Lu J, Wang Y, Gui Y, Duan X, Cai Z. Ascorbate antagonizes nickel ion to regulate JMJD1A expression in kidney cancer cells. Acta Biochim Biophys Sin (Shanghai). 2012;44(4):330–8. http://dx.doi.org/10.1093/abbs/gms004
55. Pereira F, Barbáchano A, Singh PK, Campbell MJ, Muñoz A, Larriba MJ. Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle. 2012;11(6):1081–9. http://dx.doi.org/10.4161/cc.11.6.19508
56. Larkin J, Goh XY, Vetter M, Pickering L, Swanton C. Epigenetic regulation in RCC: Opportunities for therapeutic intervention? Nat Rev Urol. 2012;9(3):147–55. http://dx.doi.org/10.1038/nrurol.2011.236