NYMC Faculty Publications
SETD7 Functions as a Transcription Repressor in Prostate Cancer via Methylating FOXA1
Author Type(s)
Faculty
DOI
10.1073/pnas.2220472120
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
First Page
e2220472120
Document Type
Article
Publication Date
8-15-2023
Department
Cell Biology and Anatomy
Abstract
Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.
Recommended Citation
Wang, Z., Petricca, J., Liu, M., Zhang, S., Chen, S., Li, M., Besschetnova, A., Patalano, S., Venkataramani, K., Siegfried, K. R., Macoska, J. A., Han, D., Gao, S., Vedadi, M., Arrowsmith, C. H., He, H. H., & Cai, C. (2023). SETD7 Functions as a Transcription Repressor in Prostate Cancer via Methylating FOXA1. Proceedings of the National Academy of Sciences of the United States of America, 120 (33), e2220472120. https://doi.org/10.1073/pnas.2220472120