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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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MLL5, a histone modifying enzyme, regulates androgen receptor activity in prostate cancer cells by recruiting co-regulators, HCF1 and SET1

  • Lee, Kyoung-Hwa (Department of Urology, Seoul National University Hospital) ;
  • Kim, Byung-Chan (Department of Urology, Seoul National University Hospital) ;
  • Jeong, Chang Wook (Department of Urology, Seoul National University Hospital) ;
  • Ku, Ja Hyeon (Department of Urology, Seoul National University Hospital) ;
  • Kim, Hyeon Hoe (Department of Urology, Seoul National University Hospital) ;
  • Kwak, Cheol (Department of Urology, Seoul National University Hospital)
  • Received : 2020.08.05
  • Accepted : 2020.10.13
  • Published : 2020.12.31
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Abstract

In prostate cancer, the androgen receptor (AR) transcription factor is a major regulator of cell proliferation and metastasis. To identify new AR regulators, we focused on Mixed lineage leukemia 5 (MLL5), a histone-regulating enzyme, because significantly higher MLL5 expression was detected in prostate cancer tissues than in matching normal tissues. When we expressed shRNAs targeting MLL5 gene in prostate cancer cell line, the growth rate and AR activity were reduced compared to those in control cells, and migration ability of the knockdown cells was reduced significantly. To determine the molecular mechanisms of MLL5 on AR activity, we proved that AR physically interacted with MLL5 and other co-factors, including SET-1 and HCF-1, using an immunoprecipitation method. The chromatin immunoprecipitation analysis showed reduced binding of MLL5, co-factors, and AR enzymes to AR target gene promoters in MLL5 shRNA-expressing cells. Histone H3K4 methylation on the AR target gene promoters was reduced, and H3K9 methylation at the same site was increased in MLL5 knockdown cells. Finally, xenograft tumor formation revealed that reduction of MLL5 in prostate cancer cells retarded tumor growth. Our results thus demonstrate the important role of MLL5 as a new epigenetic regulator of AR in prostate cancer.

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References

  1. Siegel RL, Miller KD and Jemal A (2019) Cancer statistics, 2019. CA: A Cancer Journal for Clinicians 69, 7-34 https://doi.org/10.3322/caac.21551
  2. Masson S and Bahl A (2012) Metastatic castrate-resistant prostate cancer: dawn of a new age of management. BJU Int 110, 1110-1114 https://doi.org/10.1111/j.1464-410X.2012.11076.x
  3. Claessens F, Helsen C, Prekovic S et al (2014) Emerging mechanisms of enzalutamide resistance in prostate cancer. Nat Rev Urol 11, 712-716 https://doi.org/10.1038/nrurol.2014.243
  4. Cucchiara V, Yang JC, Mirone V, Gao AC, Rosenfeld MG and Evans CP (2017) Epigenomic regulation of androgen receptor signaling: potential role in prostate cancer therapy. Cancers 9, 9 https://doi.org/10.3390/cancers9010009
  5. Peterson CL and Laniel MA (2004) Histones and histone modifications. Curr Biol 14, R546-551 https://doi.org/10.1016/j.cub.2004.07.007
  6. Gaughan L, Stockley J, Wang N et al (2011) Regulation of the androgen receptor by SET9-mediated methylation. Nucleic Acids Res 39, 1266-1279 https://doi.org/10.1093/nar/gkq861
  7. Kang HB, Choi Y, Lee JM et al (2009) The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. FEBS Lett 583, 1880-1886 https://doi.org/10.1016/j.febslet.2009.05.038
  8. Varambally S, Dhanasekaran SM, Zhou M et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629 https://doi.org/10.1038/nature01075
  9. Cai C, He HH, Chen S et al (2011) Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 20, 457-471 https://doi.org/10.1016/j.ccr.2011.09.001
  10. Metzger E, Wissmann M, Yin N et al (2005) LSD1 demethylates repressive histone marks to promote androgenreceptor-dependent transcription. Nature 437, 436-439 https://doi.org/10.1038/nature04020
  11. Kang MK, Mehrazarin S, Park NH and Wang CY (2017) Epigenetic gene regulation by histone demethylases: emerging role in oncogenesis and inflammation. Oral Dis 23, 709-720 https://doi.org/10.1111/odi.12569
  12. Willmann D, Lim S, Wetzel S et al (2012) Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor. Int J Cancer 131, 2704-2709 https://doi.org/10.1002/ijc.27555
  13. Lee KH, Hong S, Kang M et al (2018) Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer. Int J Cancer 143, 2849-2861 https://doi.org/10.1002/ijc.31843
  14. Zhou P, Ding X, Wan X et al (2018) MLL5 suppresses antiviral innate immune response by facilitating STUB1-mediated RIG-I degradation. Nat Commun 9, 1243 https://doi.org/10.1038/s41467-018-03563-8
  15. Deng LW, Chiu I and Strominger JL (2004) MLL 5 protein forms intranuclear foci, and overexpression inhibits cell cycle progression. Proc Natl Acad Sci U S A 101, 757-762 https://doi.org/10.1073/pnas.2036345100
  16. Ali M, Rincon-Arano H, Zhao W et al (2013) Molecular basis for chromatin binding and regulation of MLL5. Proc Natl Acad Sci U S A 110, 11296-11301 https://doi.org/10.1073/pnas.1310156110
  17. Zhang Y, Wong J, Klinger M, Tran MT, Shannon KM and Killeen N (2009) MLL5 contributes to hematopoietic stem cell fitness and homeostasis. Blood 113, 1455-1463 https://doi.org/10.1182/blood-2008-05-159905
  18. Yap DB, Walker DC, Prentice LM et al (2011) Mll5 is required for normal spermatogenesis. PLoS One 6, e27127 https://doi.org/10.1371/journal.pone.0027127
  19. Mas YMS, Barbon M, Teyssier C et al (2016) The human mixed lineage leukemia 5 (MLL5), a sequentially and structurally divergent SET domain-containing protein with no intrinsic catalytic activity. PLoS One 11, e0165139 https://doi.org/10.1371/journal.pone.0165139
  20. Zhou P, Wang Z, Yuan X et al (2013) Mixed lineage leukemia 5 (MLL5) protein regulates cell cycle progression and E2F1-responsive gene expression via association with host cell factor-1 (HCF-1). J Biol Chem 288, 17532-17543 https://doi.org/10.1074/jbc.M112.439729
  21. Wysocka J, Myers MP, Laherty CD, Eisenman RN and Herr W (2003) Human Sin3 deacetylase and trithoraxrelated Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev 17, 896-911 https://doi.org/10.1101/gad.252103
  22. Mora GR and Mahesh VB (1999) Autoregulation of the androgen receptor at the translational level: Testosterone induces accumulation of androgen receptor mrna in the rat ventral prostate polyribosomes. Steroids 64, 587-591 https://doi.org/10.1016/S0039-128X(99)00037-9
  23. Coutinho I, Day TK, Tilley WD and Selth LA (2016) Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence. Endocr Relat Cancer 23, T179-T197 https://doi.org/10.1530/ERC-16-0422
  24. Lu S, Tsai SY and Tsai MJ (1997) Regulation of androgendependent prostatic cancer cell growth: androgen regulation of CDK2, CDK4, and CKI p16 genes. Cancer Res 57, 4511-4516
  25. Liao X, Thrasher JB, Pelling J, Holzbeierlein J, Sang Q-XA and Li B (2003) Androgen stimulates matrix metalloproteinase-2 expression in human prostate cancer. Endocrinology 144, 1656-1663 https://doi.org/10.1210/en.2002-0157
  26. Kim EY, Jin BR, Chung TW et al (2019) 6-sialyllactose ameliorates dihydrotestosterone-induced benign prostatic hyperplasia through suppressing VEGF-mediated angiogenesis. BMB Rep 52, 560-565 https://doi.org/10.5483/bmbrep.2019.52.9.113
  27. Linder S, van der Poel HG, Bergman AM, Zwart W and Prekovic S (2018) Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond. Endocr Relat Cancer 26, R31-R52 https://doi.org/10.1530/erc-18-0289
  28. Altintas DM, Rouault JP, Samarut J et al (2012) Direct cooperation between androgen receptor and E2F1 reveals a common regulation mechanism for androgen-responsive genes in prostate cells. Mol Endocrinol 26, 1531-1541 https://doi.org/10.1210/me.2012-1016
  29. Sharma A, Yeow W-S, Ertel A et al (2010) The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 120, 4478-4492 https://doi.org/10.1172/JCI44239
  30. Narayanan A, Ruyechan WT and Kristie TM (2007) The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection. Proc Natl Acad Sci U S A 104, 10835-10840 https://doi.org/10.1073/pnas.0704351104
  31. Schrecengost R and Knudsen KE (2013) Molecular pathogenesis and progression of prostate cancer. Semin Oncol 40, 244-258 https://doi.org/10.1053/j.seminoncol.2013.04.001