Prostate cancer (PCa) is one of the most common cancers in men globally. While the initiation and development of PCa depend on the activity of androgen receptor (AR), a ligand-dependent transcription factor nuclear receptor, loss of expressions of the context-specific tumor suppressors are also critical events that facilitate the progression of PCa to a more malignant form, castration-resistant prostate cancer (CRPC). Zinc finger and BTB domain containing transcription repressors, such as ZBTB7A and ZBTB16, have recently been reported as tumor suppressors that play important functions to prevent the progression of PCa, and mutations and/or deep deletions of these genes can be found in over 5% of PCa patient samples. ZBTB7A, also known as LRF/POKEMON, consists of a protein-protein interacting BTB domain at N-terminus and DNA binding zinc fingers at C-terminus. Even though ZBTB7A has been identified as a proto-oncogene in some other cancer types, a recent study using a transgenic mouse model indicates that it functions as a tumor suppressor in PCa and loss of its expression can drive the development of aggressive invasive tumor in Pten-null prostate epithelial cells by bypassing the Pten-loss induced cellular senescence. In this study, using combined ChIP-seq and RNA-seq analyses in PCa cells, we have precisely mapped the binding sites of ZBTB7A and identified its directly regulated genes. Interestingly, the ZBTB7A-repressed genes were enriched for the activation function of E2F and MYC, suggesting that ZBTB7A may suppress their oncogenic activities in PCa cells. Since both ZBTB7A and ZBTB16 have been reported to negatively regulate AR signaling, we next determined how ZBTB7A chromatin binding in PCa cells globally impacts the transcriptional activity of AR. By co-analyzing the previous reported AR cistrome database in PCa cells, we showed that a significant portion of ZBTB7A binding sites overlapped with AR binding sites, particularly at promoter region. Using the unbiased Binding and Expression Target Analysis (BETA), we further showed that these ZBTB7A and AR overlapping sites were significantly associated with the repression activity of AR on gene transcription. By co-immunoprecipitation assays, we demonstrated that ZBTB7A can physically interact with AR and Rb, suggesting that ZBTB7A may be an additional component of the AR repressor complex. Moreover, we have also identified a subset of long non-coding RNAs (lncRNAs), as novel AR-repressed genes and showed that ZBTB7A contributes to the suppression activity of AR on a PCa-specific lncRNA, PCAT-1. Finally, we have also showed that ZBTB7A functions to suppress CRPC tumor growth in vitro and in vivo. Overall, our study has provided novel molecular insights for ZBTB7A function in PCa cells and demonstrated globally its critical role in mediating the transcriptional repression activity of AR.
Citation Format: Dong Han, Sujun Chen, Wanting Han, Shuai Gao, Jude Owiredu, Susan C. Patalano, Jill A. Macoska, Hansen H. He, Changmeng Cai. ZBTB7A mediates the transcriptional repression activity of androgen receptor in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3482.