Study of the Coactivator Function of Lysine-Specific Demethylase 1 for AR-Dependent Transcription Regulation
Abstract
Scientific Objective and Rationale: Male hormone androgen is the fuel that drives the disease progression in prostate cancer (PCa). Biologically, androgen binds to a nuclear receptor called androgen receptor (AR). AR will translocate to the nucleus and form transcriptional machinery to regulate gene expression. Therefore, hormonal therapies (including chemical or surgical castration that disrupts this pathway) stand in the mainstream of PCa therapy. Unfortunately, those therapies eventually fail, and the disease relapses to a deadly stage, called castration-resistant prostate cancer (CRPC). Mounting evidence shows that AR activity is restored at this stage. Great efforts have been made to understand the regulation of AR activity, and several key transcriptional factors have been shown to collaborate with AR to regulate gene transcription. Our lab recently found that lysine specific demethylase 1 (LSD1) could function as a critical coactivator for AR activity. As LSD1 binding sites overlap with AR binding on AR-stimulated gene loci and as inhibiting LSD1 substantially impairs AR-activated genes, I propose in this study to elucidate the molecular basis of how LSD1 collaborates with AR to orchestrate its transcription program and drive PCa growth. Career Goals: I am pursuing postdoctoral research training in the laboratory of Dr. Steven Balk, M.D., Ph.D., at Beth Israel Deaconess Medical Center (BIDMC)/Harvard Medical School. My career goal is to develop into a successful independent investigator working in the PCa research field. Working in Dr. Balk s lab is providing me with enormous perspective and the opportunity to acquire the skills needed for being a scientist in the PCa field. The lab has for a long time focused on integrated studies in CRPC, especially investigating the mechanisms underlying the resistance to androgen deprivation therapies. My mentor, Dr. Balk, has been very committed in providing excellent training and has had many successes in training researchers in the PCa field. I will be conducting my research work in an environment where basic research intimately intersects with clinical investigations, and exchanging of novel ideas and research advances is actively happening. Besides one-on-one meetings with Dr. Balk, I will be attending and making presentations in lab meetings, journal clubs, joint P01 meetings, prostate cancer SPORE meetings, and a series of BIDMC cancer center seminars. I will gain scientific training from many different perspectives with all these activities. The proposed work in this application receives full support from Dr. Balk. With our lab s expertise in studying molecular events involved in PCa and all easily accessible resources on the site, I am confident I will achieve the project fruitfully. Applicability of the Research: In this study, we are focusing on studying a key protein, LSD1, that appears to be positively regulating AR activity in a global manner. We aim to identify the novel components in the LSD1 complex and the non-canonical substrates of LSD1 that are responsible for upregulating AR activity. This study is of special importance for patients at the CRPC stage, as AR activity is restored and the molecular culprit is not clear. As inhibitors targeting LSD1 are being developed and entering clinical trials for small cell lung cancer and acute myeloid leukemia, it is urgent to elucidate the molecular interaction between LSD1 and AR in order to provide a further basis for targeting LSD1 in PCa. The potential risks of targeting could be side effects from the non-specificity, which can be minimized by extensive functional study of LSD1. The proposed study may take up to 2 years, after which, we will continue to perform analysis on targeting LSD1. Contributions of This Study: The output from this proposed study would significantly further our understanding on how AR activity is regulated in PCa. This is the core issue needed to be solved in CR
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510554
Entities
People
- Shuai Gao
Organizations
- United States Army
- University of Massachusetts Boston