Date of Award

12-2023

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Changmeng Cai

Second Advisor

Shuai Gao

Third Advisor

Jill Macoska, Shaija Pathania, Xin Yuan

Abstract

Prostate cancer (PCa) is one of the most common cancers and the highest cancer-related death in American men. Androgen receptor (AR) plays a critical role in PCa development and progression, and androgen deprivation therapy (ADT) is the first-line therapy for PCa patients. Although ADT and AR signaling inhibitors initially exhibit efficacy in suppressing tumor growth, PCa eventually develops in an advanced stage called castration-resistant prostate cancer (CRPC) due to multiple mechanisms. Recent research studies have highlighted the significance of epigenetic aberrations in driving CRPC development and drug resistance. As a pivotal epigenetic modifier, lysine-specific demethylase (LSD1/KDM1A) is highly expressed in various types of cancers including PCa. Our previous studies have shown that LSD1 functions as an androgen receptor (AR) co-activator, and demethylates forkhead box protein A1 (FOXA1) in PCa. LSD1 inhibitors have been utilized in several clinical trials in different malignancies including lung cancer, hematologic cancers, and Ewing sarcomas, but its influence at the global level remains not fully understood in PCa due to limited in vivo studies. In one of my dissertation projects, I identified that LSD1, FOXA1, and bromodomain-containing protein 4 (BRD4) form a nuclear condensate at super-enhancers (SEs), which are associated with novel oncogenic pathways in CRPC development. Therefore, I developed a novel combination treatment by co-targeting LSD1 and BRD4 to synergistically suppress CRPC tumor growth via disrupting CRPC-specific super-enhancer-associated genes. In another project, I studied LSD1 activity in African ancestry (AA) PCa, which has higher mortality and poorer prognosis than European ancestry (EA) PCa, to address the racial disparities. One of the genetic disparities observed between AA men and EA men is that AA men typically have shorter length of CAG repeats, which encodes shorter poly-glutamine tract (poly-Q) at the N-terminal domain of AR protein. The length of poly-Q is negatively correlated with the AR transcriptional activity. I demonstrated that short poly-Q AR protein has much higher stability and stronger interaction with LSD1 and another AR co-activator EZH2, and has altered transcriptome and cistrome. Furthermore, I demonstrated that LSD1 or EZH2 inhibitors can significantly suppress AA tumor growth, providing a therapeutic strategy to address racial disparities in AA PCa patients. Overall, my findings revealed that the combination treatment of LSD1 inhibition and BRD4 inhibition is a promising therapeutic approach to synergistically suppress CRPC tumor growth by disrupting CRPC-specific SEs genes and that the LSD1 inhibition in PCa patients with shorter CAG repeats of AR provides new therapeutic strategy in addressing racial disparities of PCa.

Comments

Free and open access to this Campus Access Thesis is made available to the UMass Boston community by ScholarWorks at UMass Boston. Those not on campus and those without a UMass Boston campus username and password may gain access to this thesis through resources like Proquest Dissertations & Theses Global (https://www.proquest.com/) or through Interlibrary Loan. If you have a UMass Boston campus username and password and would like to download this work from off-campus, click on the "Off-Campus UMass Boston Users

Download
Off-Campus UMass Boston Users

Share

COinS