You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2014MP49-14 SMYD3 IS RESPONSIBLE FOR ANDROGEN-INDUCED H3K4 METHYLATION IN PROSTATE CANCER CELLS Zachary Hamilton, Ruibao Chen, Xiangxing Kuang, Yiling Huang, J. Brantley Thrasher, and Benyi Li Zachary HamiltonZachary Hamilton More articles by this author , Ruibao ChenRuibao Chen More articles by this author , Xiangxing KuangXiangxing Kuang More articles by this author , Yiling HuangYiling Huang More articles by this author , J. Brantley ThrasherJ. Brantley Thrasher More articles by this author , and Benyi LiBenyi Li More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1115AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Epigenetic alteration plays a major role in prostate cancer development and progression. Histones are the key factors in modulating gene accessibility to transcription factors. Post-translational modification of the histone N-terminal tail includes methylation, acetylation, phosphorylation, ubiquitination, sumoylation, ADP-ribosylation and deamination. Of these, histone methylation is associated with either transcriptional activation (H3K4, H3K36 and H3K79) or repression (H3K9, H3K27 and H4K20). Furthermore, androgens and the androgen receptor (AR) are key factors for prostate cancer development and progression. SMYD3 is a histone methyltransferase that plays a role in transcriptional regulation. Previously, we have shown that p110β is critical for androgen-induced gene expression and cell proliferation in prostate cancer. The objective of this study was to investigate the involvement of p110β in histone methylation and prostate cancer cell proliferation. Methods In this study, we examined the effect of androgen stimulation on the global levels of H3K4a methylation in prostate cancer cells. Histone methylation was assessed in western blot assays using methylation site-specific antibodies. The involvement of p110β and SMYD3 were determined with gene specific small interference RNAs and chemical inhibitor TGX221. The direct interaction of SMYD3 with AR-downstream genes was evaluated with chromatin immunoprecipitation assay. The global levels of H3K4 methylation were assessed by immunohistochemical staining on tissue section. Results Our data revealed that H3K4me2 was significantly elevated after androgen stimulation, which was due to increased methylation but not reduced demethylation. Using the small interfering RNA approach, we further defined that out of eight H3K4 methyltransferases, SMYD3 was responsible for androgen-stimulated increase of H3K4me2 level. Meanwhile, inhibition of PI3K/p110β activity through p110β inhibitor TGX221 abolished androgen-stimulated H3K4me2 modification. Finally, prostate cancer cell-targeted delivery of p110β inhibitor TGX221 in vivo suppressed xenograft tumor growth, which is associated with reduced H3K4me2 methylation. Conclusions Taken together, this data suggests that androgen stimulates SMYD3-dependent H3K4me2 modification, which is regulated by the PI3K/p110β pathway in prostate cancer cells. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e507 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Zachary Hamilton More articles by this author Ruibao Chen More articles by this author Xiangxing Kuang More articles by this author Yiling Huang More articles by this author J. Brantley Thrasher More articles by this author Benyi Li More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...