Inhibiting Lysine-Specific Demethylase 1 Activity as a Potential Therapeutic Treatment for Castration-Resistant Prostate Cancer
Abstract
Epigenetic reprogramming induced by aberrant expression and activity of histone modifying proteins has emerged as a critical mechanism for prostate cancer resistance to AR signaling inhibition treatments. LSD1 functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 but also has a coactivator function on AR. In this project, we have shown that LSD1 broadly enhances AR chromatin binding by increasing enhancer accessibility prior to androgen stimulation through demethylating FOXA1 and stabilizing FOXA1 chromatin binding. Our comprehensive RNA-seq analyses confirmed AR and FOXA1 as major targets of LSD1in vivo. In addition to regulating AR signaling, LSD1 and BRD4 can form nuclear condensates and are co-enriched at the super-enhancers that are associate with oncogenic transcription factor genes, such as MYC. We show that the combination treatment of LSD1 inhibitor and BET inhibitors can act in synergy in treating CRPC models.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1191203
Entities
People
- Changmeng Cai
Organizations
- University of Massachusetts Boston