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 non-histone proteins and can function as a transcriptional corepressor and coactivator.
LSD1 has been reported to act as a coactivator of androgen receptor (AR) in prostate cancer (PCa) 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 PCa 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 PCa (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 (SE) 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 SEs. These results provide mechanistic and therapeutic insights for co-targeting two key epigenetic factors and could be rapidly translated in the clinic for CRPC patients.
Cancer research. 2023 Mar 06 [Epub ahead of print]
Muqing Li, Mingyu Liu, Wanting Han, Zifeng Wang, Dong Han, Susan Patalano, Jill A Macoska, Steven P Balk, Housheng Hansen He, Eva Corey, Shuai Gao, Changmeng Cai
Uiversity of Massachusetts Boston, Boston, MA, United States., University of Massachusetts Boston, Boston, MA, United States., Fred Hutchinson Cancer Center, Seattle, WA, United States., University of Massachusetts Amherst, Boston, MA, United States., Beth Israel Deaconess Medical Center, Boston, MA, United States., Princess Margaret Cancer Centre, Toronto, Ontario,, Canada., University of Washington, SEATTLE, WA, United States., New York Medical College, Valhalla, United States.