Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, Canada.
Cancer Res. 2019 Oct 15;79(20):5260-5271. doi: 10.1158/0008-5472.CAN-19-0815. Epub 2019 Aug 23.
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) and , 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.
抑癌基因的表达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，如 ZBTB7A 和 ZBTB16，最近被鉴定为肿瘤抑制因子，在阻止前列腺癌进展中发挥重要作用。在这项研究中，我们使用前列腺癌细胞的联合 ChIP-seq 和 RNA-seq 分析来鉴定直接受 ZBTB7A 抑制的基因，这些基因富集了 E2F 的转录靶点，并确定雄激素受体（AR）在这些 E2F 靶点的转录抑制中起着关键作用。AR 招募视网膜母细胞瘤蛋白（Rb）是增强 E2F-Rb 转录抑制复合物的必需条件。此外，ZBTB7A 被 AR 快速招募到 E2F-Rb 结合位点，并负调控 E2F1 在 DNA 复制基因上的转录活性。最后，ZBTB7A 抑制去势抵抗性前列腺癌（CRPC）的生长，并且 ZBTB7A 的过表达与高剂量睾酮治疗协同作用，有效地预防了 CRPC 的复发。总的来说，这项研究提供了 ZBTB7A 在 CRPC 细胞中作用的新分子见解，并证明了它在介导 AR 的转录抑制活性方面的关键作用。意义：ZBTB7A 被 AR 招募到 E2F-Rb 结合位点，并负调控 E2F1 在 DNA 复制基因上的转录活性。
