Increased Expression in Castration-Resistant Prostate Cancer Rapidly Induces AR Signaling Reprogramming With the Collaboration of EZH2

Authors

Maryam Labaf, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.
Muqing Li, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.
Lily Ting, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.
Breelyn Karno, Department of Medicine, Vanderbilt University, Nashville, TN, United States.
Songqi Zhang, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.
Shuai Gao, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States.Follow
Susan Patalano, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.
Jill A. Macoska, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.
Kourosh Zarringhalam, Department of Mathematics, University of Massachusetts Boston, Boston, MA, United States.
Dong Han, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.
Changmeng Cai, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, United States.

Author Type(s)

Faculty

DOI

10.3389/fonc.2022.1021845

Journal Title

Frontiers in Oncology

First Page

1021845

Document Type

Article

Publication Date

1-1-2022

Department

Cell Biology and Anatomy

Abstract

Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.

Recommended Citation

Labaf, M., Li, M., Ting, L., Karno, B., Zhang, S., Gao, S., Patalano, S., Macoska, J. A., Zarringhalam, K., Han, D., & Cai, C. (2022). Increased Expression in Castration-Resistant Prostate Cancer Rapidly Induces AR Signaling Reprogramming With the Collaboration of EZH2. Frontiers in Oncology, 12, 1021845. https://doi.org/10.3389/fonc.2022.1021845