UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications
UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications
复制标题
UHRF1通过KDM4C介导的染色质修饰促进前列腺癌中雄激素受体调节的CDC6转录和抗雄激素受体耐药性
DOI：
10.1016/j.canlet.2021.07.012
复制
发表时间：
2021-07-13
期刊：
影响因子：
9.7
通讯作者：
Li, Xiong
中科院分区：
文献类型：
--
作者：
Gao, Yingxue;Liu, Yijun;Li, Xiong
癌基因uhrf1和CDC6在耐药中起重要作用。在本研究中，我们发现uhrf1介导雄激素受体(AR)调节前列腺癌细胞CDC6的转录。在前列腺癌组织和细胞系中，uhrf1和CDC6水平同时上调，这与较差的存活率有关。Uhrf1沉默通过抑制CDC6基因的表达，显著提高比卡鲁胺对小鼠移植瘤的细胞毒性和抗前列腺癌的疗效。Uhrf1通过与CDC6启动子中雄激素反应元件(ARE)附近的CCAAT基序结合，促进AR调控的CDC6转录。我们进一步发现，uhrf1通过招募H3K9me2/3特异性去甲基转移酶KDM4C并改变强烈的异染色质状态，促进雄激素依赖的染色质占据AR蛋白。总之，我们首次发现uhrf1通过一种新的染色质修饰机制促进AR调节的CDC6转录，并在前列腺癌的抗AR耐药性中发挥作用。同时靶向AR和uhrf1可能是治疗前列腺癌的一种新的、有前途的治疗方法。
The UHRF1 and CDC6, oncogenes play critical roles in therapeutic resistance. In the present study, we found that UHRF1 mediates androgen receptor (AR)-regulated CDC6 transcription in prostate cancer cells. In prostate cancer tissues and cell lines, levels of UHRF1 and CDC6 were simultaneously upregulated, and this was associated with worse survival. UHRF1 silencing significantly promoted the cytotoxicity and anti-prostate cancer efficacy of bicalutamide in mouse xenografts by inhibiting CDC6 gene expression. UHRF1 promoted AR regulated CDC6 transcription by binding to the CCAAT motif near the androgen response element (ARE) in the CDC6 promoter. We further found that UHRF1 promoted androgen-dependent chromatin occupancy of AR protein by recruiting the H3K9me2/3-specific demethyltransferase KDM4C and modifying the intense heterochromatin status. Altogether, we found for the first time that UHRF1 promotes AR-regulated CDC6 transcription through a novel chromatin modification mechanism and contributes to anti-AR drug resistance in prostate cancer. Targeting AR and UHRF1 simultaneously may be a novel and promising therapeutic modality for prostate cancer.