Comprehensive Investigation of AR mRNA Interactome in Advanced Prostate Cancer
Abstract
Scientific Objective: Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-related death among American men. The androgen receptor (AR) transcription factor is a master regulator of normal glandular homeostasis in the prostate, as well as growth and survival of prostate cancer cells. Therefore, AR-targeted therapies are effective for improving overall survival of patients with advanced prostate cancer that is incurable by surgery or radiation. However, the current primary treatment for advanced prostate cancer by hormone deprivation therapy eventually becomes castration-resistant prostate cancer with no effective treatment options, highlighting the urgent need to identify and develop better therapeutics to target advanced prostate cancer. The main cause leading to castration resistance is aberrant AR reactivation, including AR overexpression, mutation, changes in coregulator proteins, and steroid metabolism. Previous investigation identified AR gene amplification in tumor cells from castration-resistant patients, suggesting genomic changes of AR gene lead to increased AR mRNA transcript and AR protein expression. Gene expression can be regulated at different levels, such as genomic level, transcriptional level, post-transcriptional level, and post-translational level. Thus, genomic and transcriptomic changes insufficiently predict prostate cancer biology, and AR DNA, AR mRNA, and AR protein expression levels frequently do not correlate. Non-coding RNAs and RNA binding proteins could bind mRNA and regulate gene expression at the post-transcriptional level, thus participating in the cellular process and disease progression. Previous studies have reported the regulation of AR expression at the genomic level, transcriptional level, and post-translational level. However, the post-transcriptional regulation of AR mRNA by its interacted non-coding RNAs and RNA binding proteins, is largely unknown. In this proposed study, we will comprehensively profile AR mRNA interacted non-coding RNAs and RNA binding proteins for the first time and further identify key AR mRNA regulators among the interacted factors. Moreover, we will test the therapeutic efficacy of targeting these key AR mRNA interactors in the castration-resistance mice model. The proposed study will address several FY22 PCRP Overarching Challenges. The investigation of AR mRNA interacted non-coding RNA and RNA binding proteins in castration-resistant prostate cancer cells will exceptionally expand the scientific knowledge about AR regulation at the post-transcriptional level for the first time, which will define the biology of prostate cancer progression to the lethal castration resistance prostate cancer. The bioinformatic analysis of the AR mRNA interactors’ regulation of AR and their relevance to castration resistance will help to identify the biomarkers that could predict therapy resistance. What’s more, the result from testing the therapeutic efficacy of targeting these key AR mRNA interactors will provide important preclinical data to support the initiation of clinical trials that target these AR mRNA interactors for the treatment of castration-resistant prostate cancer, leading to the development of new treatments that improve outcomes for men with the lethal castration-resistant prostate cancer. Applicability of Research: Successful completion of the proposed studies will provide two immediate important clinical applications. This study will identify key AR mRNA interactors that participate in castration resistance. Some of these important AR mRNA interactors can be utilized as diagnostic and prognostic markers for prostate cancer patients who are receiving hormone deprivation therapy by analyzing large-scale transcriptomic and clinical data from prostate cancer patients. Second, the results of this study will identify some AR mRNA interactors as promising new therapeutic targets for patients with cas
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310491
Entities
People
- Yongyong Yang
Organizations
- Northwestern University
- United States Army