The critical roles of histone modification in anti-androgen receptor herbal drug and cancer therapy

• Main Authors: Ching Yuan Wu, 吳清源
• Other Authors: H. Y. Kang
• Format: Others
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/99694397869591610617

博士 === 長庚大學 === 臨床醫學研究所 === 100 === Most eukaryotes make nucleosomes to compact the genome by wrapping their DNA around histones (H3, H4, H2A, H2B). When DNA suffers from stimulating with several factors or damage by stress, nucleosomes will release to allow access for active processes such as transcription, replication and DNA damage repair. Importantly, these different modifications of histones can control modulation of chromatin to regulate DNA accessibility for other proteins by modulation of nucleosomal structure or by serving a platform to recruit other proteins. DNA damage and hormone play very important roles in the initiation and development of cancer and involve several different modifications of histones. Development and progression of prostate cancer are intimately associated with androgen receptor (AR) signaling. The emergence of hormone-refractory prostate cancer and consequent failure of conventional androgen deprivation therapies make it necessary to bypass hormonal resistance by targeting the same signaling pathway at new intervention points. First, we describe a novel mechanism whereby cryptotanshinone down-regulates AR signaling via functional inhibition of LSD1-mediated demethylation of H3K9 and represses the transcriptional activity of AR. Our data suggest that cryptotanshinone can be developed as a potential therapeutic agent for prostate cancer. DNA damage response (DDR) is an important surveillance mechanism to maintain the integrity of human genome in response to genotoxic stress. Histone variant H2AX is a critical sensor that undergoes phosphorylation at serine 139 (S139) upon genotoxic stress, which provides a docking site to recruit mediator of DNA damage checkpoint protein 1 (MDC1) and DNA repair protein complex to sites of DNA breaks for DNA repair. Second, we show that monoubiquitination of H2AX induced by ring finger protein 2 (RNF2) is required for the recruitment of active ataxia-telangiectasia mutated (ATM) to DNA damage foci, thus affecting the formation of γ-H2AX. Importantly, defect in monoubiquitination of H2AX profoundly enhances ionizing radiation (IR) sensitivity. Our study therefore suggests that monoubiquitination of H2AX is an important step for DNA damage response and may have important clinical implications for the treatment of cancers. Our study will provide a better understanding how the modification of histone is involved in anti-cancer therapy, and may have a potential to discover a novel compound for cancer treatment by targeting the modification of histone.