ZBTB7A Mediates the Transcriptional Repression Activity of the Androgen Receptor in Prostate Cancer
ZBTB7A Mediates the Transcriptional Repression Activity of the Androgen Receptor in Prostate Cancer
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DOI：
10.1158/0008-5472.can-19-0815
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发表时间：
2019-10-15
期刊：
影响因子：
11.2
通讯作者：
Cai, Changmeng
中科院分区：
文献类型：
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作者：
Han, Dong;Chen, Sujun;Cai, Changmeng
背景特异性肿瘤抑制因子表达的缺失是促进前列腺癌发展的关键事件。锌指和BTB结构域转录抑制因子ZBTB 7A和ZBTB 16是近年来发现的在预防前列腺癌进展中发挥重要作用的肿瘤抑制因子。在这项研究中，我们使用了前列腺癌细胞的ChIP-seq和RNA-seq分析来鉴定直接ZBTB 7A抑制的基因，这些基因富含E2 F的转录靶点，并鉴定了雄激素受体（AR）在这些E2 F靶点的转录抑制中发挥了关键作用。视网膜母细胞瘤蛋白（Rb）的AR募集需要加强E2 F-Rb转录抑制复合物。此外，ZBTB 7A被AR迅速募集到E2 F-Rb结合位点，并负调控E2 F1对DNA复制基因的转录活性。最后，ZBTB 7A在体外和体内抑制去势抵抗性前列腺癌（CRPC）的生长，并且ZBTB 7A的过表达与高剂量睾酮治疗协同作用，以有效地防止CRPC的复发。总体而言，这项研究提供了新的分子见解ZBTB 7A在CRPC细胞中的作用，并在全球范围内证明其在介导AR的转录抑制活性的关键作用。意义：ZBTB 7A被招募到E2 F-Rb结合位点的AR和负调控的转录活性E2 F1的DNA复制基因。
Loss of expression of context-specific tumor suppressors is a critical event that facilitates the development of prostate cancer. Zinc finger and BTB domain containing transcriptional repressors, such as ZBTB7A and ZBTB16, have been recently identified as tumor suppressors that play important roles in preventing prostate cancer progression. In this study, we used combined ChIP-seq and RNA-seq analyses of prostate cancer cells to identify direct ZBTB7A-repressed genes, which are enriched for transcriptional targets of E2F, and identified that the androgen receptor (AR) played a critical role in the transcriptional suppression of these E2F targets. AR recruitment of the retinoblastoma protein (Rb) was required to strengthen the E2F-Rb transcriptional repression complex. In addition, ZBTB7A was rapidly recruited to the E2F-Rb binding sites by AR and negatively regulated the transcriptional activity of E2F1 on DNA replication genes. Finally, ZBTB7A suppressed the growth of castration-resistant prostate cancer (CRPC) in vitro and in vivo, and overexpression of ZBTB7A acted in synergy with high-dose testosterone treatment to effectively prevent the recurrence of CRPC. Overall, this study provides novel molecular insights of the role of ZBTB7A in CRPC cells and demonstrates globally its critical role in mediating the transcriptional repression activity of AR.Significance: ZBTB7A is recruited to the E2F-Rb binding sites by AR and negatively regulates the transcriptional activity of E2F1 on DNA replication genes.