Targeting FOXA1 Methylation in Castration-Resistant Prostate Cancer
Abstract
Androgen, one type of male hormone, is critical for prostate cancer development. Androgen exerts its function through binding to its receptor protein, androgen receptor (called AR), which can subsequently bind to the regulatory sites of certain genes in chromatin and turn on their expression to promote prostate cancer development. Patients with metastatic prostate cancer can be treated with androgen deprivation therapies to block AR function. However, the tumors will eventually develop resistance in a more aggressive stage of cancer, termed castration-resistant prostate cancer (CRPC), where AR function is restored. Recently, more aggressive androgen deprivation therapies were introduced using two FDA-approved drugs (abiraterone and enzalutamide) to treat CRPC. The majority of CRPC patients respond initially to these treatments, but most relapse by 1 year. AR activity is once again restored in the majority of patients. Therefore, there is a pressing need for developing new treatment strategies to target the reactivation of AR. The AR access to chromatin is dependent on the binding of another factor, FOXA1 (Forkhead Box Protein A1), which is called a pioneer factor. FOXA1 has the unique ability to bind to the compact form of chromatin, which is not accessible by most transcription factors. FOXA1 binding can decompact the chromatin and open the site for the subsequent AR binding. Recent studies revealed that FOXA1 is frequently mutated or altered in over 40% of CRPC, resulting in overexpression or gained activity of FOXA1. Therefore, FOXA1 alterations appear to be a major mechanism for restoring AR activity and promoting CRPC progression. However, it is extremely challenging to therapeutically target FOXA1. In a preliminary study, we found FOXA1 is specifically modified at its lysine 270 amino acid residual (this modification is called methylation), and this modification can prevent FOXA1 chromatin binding. However, in prostate cancer cells this modification is removed by LSD1 (lysine-specific demethylase 1), thus enhancing FOXA1 chromatin binding. Therefore, we propose to fully characterize the role and the molecular function of this modification in driving chromatin opening and AR (with its cancer-specific isoforms) chromatin binding. Moreover, we will assess in animal models how this FOXA1 modification affects CRPC tumor response to enzalutamide treatment. Meanwhile, we will also try to identify the protein enzymes that are responsible to carry this modification reaction on FOXA1 and additional proteins that may participate in the process to remove the modification. Finally, we will assess treatments that can enhance FOXA1 methylation in enzalutamide-resistant CRPC models. Our proposed study, if successfully, will provide novel insights in the molecular basis of FOXA1 chromatin binding and demonstrate a novel strategy to target FOXA1 for CRPC treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110267
Entities
People
- Changmeng Cai
Organizations
- United States Army
- University of Massachusetts Boston