LSD1 Inhibition Disrupts Super-Enhancer-Driven Oncogenic Transcriptional Programs in Castration-Resistant Prostate Cancer

Authors

Muqing Li, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Mingyu Liu, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.Follow
Wanting Han, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Zifeng Wang, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Dong Han, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Susan Patalano, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Jill A. Macoska, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Steven P. Balk, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Housheng Hansen He, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Eva Corey, Department of Urology, University of Washington, Seattle, Washington.
Shuai Gao, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.Follow
Changmeng Cai, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.

Author Type(s)

Faculty

DOI

10.1158/0008-5472.CAN-22-2433

Journal Title

Cancer Research

First Page

1684

Last Page

1698

Document Type

Article

Publication Date

5-15-2023

Department

Cell Biology and Anatomy

Abstract

UNLABELLED: The lysine demethylase LSD1 (also called KDM1A) plays important roles in promoting multiple malignancies including both hematologic cancers and solid tumors. LSD1 targets histone and nonhistone proteins and can function as a transcriptional corepressor or coactivator. LSD1 has been reported to act as a coactivator of androgen receptor (AR) in prostate cancer and to regulate the AR cistrome via demethylation of its pioneer factor FOXA1. A deeper understanding of the key oncogenic programs targeted by LSD1 could help stratify prostate cancer patients for treatment with LSD1 inhibitors, which are currently under clinical investigation. In this study, we performed transcriptomic profiling in an array of castration-resistant prostate cancer (CRPC) xenograft models that are sensitive to LSD1 inhibitor treatment. Impaired tumor growth by LSD1 inhibition was attributed to significantly decreased MYC signaling, and MYC was found to be a consistent target of LSD1. Moreover, LSD1 formed a network with BRD4 and FOXA1 and was enriched at super-enhancer regions exhibiting liquid-liquid phase separation. Combining LSD1 inhibitors with BET inhibitors exhibited strong synergy in disrupting the activities of multiple drivers in CRPC, thereby inducing significant growth repression of tumors. Importantly, the combination treatment showed superior effects than either inhibitor alone in disrupting a subset of newly identified CRPC-specific super-enhancers. These results provide mechanistic and therapeutic insights for cotargeting two key epigenetic factors and could be rapidly translated in the clinic for CRPC patients. SIGNIFICANCE: LSD1 drives prostate cancer progression by activating super-enhancer-mediated oncogenic programs, which can be targeted with the combination of LSD1 and BRD4 inhibitors to suppress the growth of CRPC.

Recommended Citation

Li, M., Liu, M., Han, W., Wang, Z., Han, D., Patalano, S., Macoska, J. A., Balk, S. P., He, H. H., Corey, E., Gao, S., & Cai, C. (2023). LSD1 Inhibition Disrupts Super-Enhancer-Driven Oncogenic Transcriptional Programs in Castration-Resistant Prostate Cancer. Cancer Research, 83 (10), 1684-1698. https://doi.org/10.1158/0008-5472.CAN-22-2433