Inhibiting Lysine Specific Demethylase 1 Activity as a Potential Therapeutic Treatment for Castration-Resistant Prostate Cancer
Abstract
Reactivation of androgen receptor (AR) signaling 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. In this project, we have shown that LSD1 broadly enhances AR chromatin binding and activity by increasing enhancer accessibility prior to androgen stimulation through demethylating the pioneer factor FOXA1 and stabilizing FOXA1 chromatin binding. Moreover, in addition to regulating AR signaling, LSD1 and BRD4 are coenriched at the super-enhancers that are associate with oncogenic transcription factor genes, such as MYC, and regulate their expressions. We are currently testing the combination treatment of LSD1 inhibitor and BET inhibitors in CRPC models. Our findings provide novel therapeutic insights on developing LSD1 inhibitor treatment in CRPC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1161547
Entities
People
- Changmeng Cai
Organizations
- Boston University