Inhibiting Lysine-Specific Demethylase 1 Activity as a Potential Therapeutic Treatment for Castration Resistant Prostate Cancer
Abstract
Persistent AR expression and activity are found in the majority of castration-resistant prostate cancer (CRPC) and CRPC resistant to enzalutamide, indicating a pressing need for further development of novel AR-targeted therapies. Lysine-Specific Demethylase 1 (LSD1)functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4) but also has a coactivator function on AR with unclear mechanism. We showed that LSD1 broadly regulates AR function by possibly affecting enhancer availability prior to androgen stimulation through interaction with pioneer factor FOXA1. LSD1 inhibition globally disrupted FOXA1 chromatin binding prior to androgen treatment and thus impaired further AR recruitment, resulting in the global inhibition of AR transcriptome. In this project, we have then discovered that methylated lysine 270 (K270) residue of FOXA1 is a direct substrate of LSD1and its demethylation stabilized AR recruitment. Our findings provide novel mechanistic insights on the role of LSD1 in PCa development and suggest that LSD1 inhibition may be a new therapeutic strategy in treating AR-driven CRPC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1119059
Entities
People
- Changmeng Cai
Organizations
- University of Massachusetts