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 for stabilizing FOXA1 chromatin binding. In this report, we have shown that the K270 demethylation expands FOXA1 chromatin binding and subsequently alters AR binding, particularly in response to enzalutamide treatment. Furthermore, we have also identified SETD7 as the primary methyltransferase of K270 and demonstrated that reduced expression of SETD7 in CRPC cells can reprogram FOXA1 cistrome, promoting cancer progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2023
- Accession Number
- AD1209658
Entities
People
- Changmeng Cai
Organizations
- University of Massachusetts Boston