Date of Award
8-2023
Document Type
Open Access Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biology/Molecular, Cellular, and Organismal Biology
First Advisor
Changmeng Cai
Second Advisor
Alexey Veraksa
Third Advisor
Shailja Pathania
Abstract
Prostate cancer (PCa) is a leading cause of cancer-related deaths in men worldwide. Alterations in epigenetic regulation of gene expression have emerged as key contributors to PCa development, treatment resistance and disease progression. My thesis focuses on investigating the role of lysine-specific demethylase 1 (LSD1), a critical histone modifier, in mediating epigenetic reprogramming that drives PCa progression. The dissertation comprises three projects that elucidate the mechanisms by which LSD1 can regulate PCa progression. The first project shows that LSD1 can activate the PI3K/AKT pathway in PCa cells independent of its well-established androgen receptor (AR) coactivator function. The study identifies the regulatory subunit of PI3K, p85, as a critical transcriptional target of LSD1 that mediates its effect on the PI3K/AKT pathway activation. The second project focuses on understanding the molecular mechanisms behind PCa lineage plasticity, specifically driven by the transition from FOXA1 to FOXA2, both of which are pioneer transcription factors. This study shows that FOXA2 binds to distinct classes of enhancers in multiple AR-null PCa models with different lineages and drives AP-1 reprogramming by functioning as a pioneer factor of JUN. This unique chromatin activity of FOXA2 is dependent on LSD1-mediated demethylation of FOXA2 protein. The third project highlights the role of SET domain containing lysine methyltransferase 7 (SETD7) as a transcriptional repressor in PCa by opposing LSD1 activity. The study shows that SETD7 directly methylates FOXA1 to inhibit its chromatin binding and negatively regulates the LSD1-FOXA1 oncogenic axis. Furthermore, loss of SETD7 expression in PCa can induce reprogramming of FOXA1. Taken together, our results demonstrate that LSD1/SETD7-mediated epigenetic reprogramming plays a critical role in driving PCa progression and suggest that targeting LSD1 may be a promising therapeutic strategy for the treatment of PCa. This dissertation provides new insights into the molecular mechanisms underlying PCa progression and highlights potential targets for future therapeutic interventions.
Recommended Citation
Wang, Zifeng, "LSD1-Mediated Epigenetic Reprogramming Driving Prostate Cancer Progression" (2023). Graduate Doctoral Dissertations. 861.
https://scholarworks.umb.edu/doctoral_dissertations/861