Date of Award

5-2023

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Computational Sciences

First Advisor

Changmeng Cai

Second Advisor

Kourosh Zarringhalam

Third Advisor

Rahul Kulkarni

Abstract

Appraising the crucial role of androgen receptor (AR) in prostate cancer (PCa) initiation and progression, androgen deprivation therapy (ADT) is considered the most effective therapy. However, PCa can adapt to ADT with overexpression of full-length AR (AR- FL) and constitutively active AR-V7 splice variant due to gene amplification or other mechanisms. While these events have been intensively studied, it is still unclear how AR-FL or AR-V7 overexpression may induce functionally important transcriptional re- programming. We generated stable PCa cell lines to overexpress inducible AR-FL or AR-V7 and performed combined cistrome and transcriptome analyses to dissect the role of their overexpression in driving chromosome structural and transcriptional changes. We found that overexpression of AR-FL alone in conjunction with lower androgen levels can rapidly activate a distinct transcriptional program that is enriched for DNA dam- age repair pathways and predicted the engagement of an epigenetic factor EZH2. We also found that AR-V7 can activate a distinct metastatic program by functioning as a “pioneer factor-like” protein to access compact chromatin regions. This AR-V7 unique transcription program can activate a stem cell and metastasis driver, SOX9, and lead to accelerated bone metastasis. Moreover, we also studied high-dose androgen-induced AR transcriptional repression program using single-cell RNA-seq analysis and revealed differ- ential responses in PCa tumors with Rb-proficient and deficient populations. Overall, my dissertation work has revealed the differential transcriptional reprogramming triggered by overexpression of AR-FL, AR-V7, or high-dose androgen in ADT-resistant PCa.

Comments

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