SETD7 Functions as a Transcription Repressor in Prostate Cancer via Methylating FOXA1

Authors

• Zifeng Wang, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.
• Jessica Petricca, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
• Mingyu Liu, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.Follow
• Songqi Zhang, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.
• Sujun Chen, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
• Muqing Li, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.
• Anna Besschetnova, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.Follow
• Susan Patalano, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.
• Kavita Venkataramani, Department of Biology, University of Massachusetts Boston, Boston, MA 02125.
• Kellee R. Siegfried, Department of Biology, University of Massachusetts Boston, Boston, MA 02125.
• Jill A. Macoska, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.
• Dong Han, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.
• Shuai Gao, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595.Follow
• Masoud Vedadi, Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
• Cheryl H. Arrowsmith, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
• Housheng Hansen He, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
• Changmeng Cai, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125.

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

Keywords

FOXA1, LSD1, SETD7, lysine methylation, prostate cancer

Disciplines

Medicine and Health Sciences

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