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All-trans retinoic acid (ATRA) has been widely investigated for treatments of many cancers including prostate cancer.  HOXB13 , silenced in androgen receptor-negative (AR − ) prostate cancer cells, plays a role in AR −  prostate cancer cell growth arrest. In this study we intended to elucidate the mechanisms that are involved in the proliferation inhibition of AR −  prostate cancer cells triggered by ATRA. We discovered that ATRA was able to induce the growth arrest and to increase  HOXB13  expression in AR −  prostate cancer cells. Both EZH2 and DNMT3b participated in the repression of  HOXB13  expression through an epigenetic mechanism involving DNA and histone methylation modifications. Specifically, EZH2 recruited DNMT3b to  HOXB13  promoter to form a repression complex. Moreover, ATRA could upregulate  HOXB13  through decreasing EZH2 and DNMT3b expressions and reducing their interactions with the  HOXB13  promoter. Concurrently, the methylation level of the  HOXB13  promoter was reduced upon the treatment of ATRA. Results from this study implicated a novel effect of ATRA in inhibition of the growth of AR −  resistant human prostate cancer cells through alteration of  HOXB13  expression as a result of epigenetic modifications.

ATRA Inhibits the Proliferation of DU145 Prostate Cancer Cells through Reducing the Methylation Level of HOXB13 Gene