Targeting FOXA1 Methylation in Castration-Resistant Prostate Cancer
Abstract
Metastatic prostate cancer inevitably relapses to the castration-resistant stage (CRPC) after standard or more aggressive androgen deprivation therapies, with restored AR signaling, indicating a pressing need for the development of novel therapies to target AR reactivation.FOXA1 functions as a pioneer factor and its chromatin binding is required for AR access to enhancers. We have recently discovered that FOXA1 is methylated at lysine 270 (K270), which is demethylated by LSD1, and that the demethylation of K270 is critical to stabilize FOXA1 chromatin binding in prostate cancer cells. In this report, we have shown that the K270methylation is dramatically decreased in CRPC adapted to enzalutamide treatment and that increased levels of unmethylated K270 may lead to AR cistrome reprogramming. Moreover, we have also identified and validated SETD7 and MLL1 as methyltransferases of K270 and demonstrated that they function to oppose the effect of LSD1 on the chromatin binding of FOXA1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1191157
Entities
People
- Changmeng Cai
Organizations
- University of Massachusetts Boston