HIF employs CHD4 to stimulate RNA polymerase Ⅱ recruitment in response to hypoxia
作者单位：Biomedical Translational Research Institute Jinan University Department of Pathology UT Southwestern Medical Center School of Medicine Jinan University
会议名称：《中国生物化学与分子生物学会2019年全国学术会议暨学会成立四十周年》
会议日期：2019年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
关 键 词：breast cancer HIF CHD4 RNA polymerase Ⅱ
摘 要：Metastatic breast cancer has high rates of relapse and mortality. The transcription factor hypoxia-inducible factor(HIF) plays a crucial role in breast cancer metastasis by inducing hundreds of the downstream target genes. RNA polymerase II is essential for HIF-mediated transactivation. However, the mechanism by which RNA polymerase Ⅱ is loaded to HIF target genes remains unknown. Based on mass spectrometry analysis, we identified epigenetic remodeler CHD4 as a novel HIF regulator. CHD4 is highly expressed in invasive breast tumors and this overexpression is significantly correlated with poor clinical outcomes in patients with breast cancer. CHD4 depletion dramatically attenuates the tumorigenic potential of breast cancer cells in colony formation, migration and invasion in vitro, and suppresses breast tumor growth and metastasis in mice. To elucidate the underlying mechanism, we performed Co-IP, RNA-seq, ChIP-qPCR and RT-qPCR assays, and found that CHD4 interacts with HIF complex at the hypoxia inducible elements(HREs) to provoke the expression of HIF target genes LOX, ANGPTL4, NDNF and VEGFA in a HIF-dependent manner. CHD4 interacts with and recruits RNA Polymerase II to the HREs, thereby promoting the formation of transcription preinitiation complex. Together, CHD4-HIF-RNA polymerase Ⅱ axis is critical for breast cancer progression and *** summary, CHD4 augments HIF-mediated breast cancer progression and metastasis, and provides a potential prognostic biomarker and therapeutic target for breast cancer.