Author ORCID Identifier

0000-0002-0703-2334

Date of Graduation

8-2022

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Wenliang Li

Committee Member

Daniel E. Frigo

Committee Member

Guangwei Du

Committee Member

Mikhail G. Kolonin

Committee Member

Rebecca Berdeaux

Committee Member

Wenbo Li

Abstract

Prostate cancer (PCa) is the second most frequent cancer and the second leading cause of mortality in men in the United States. Neuroendocrine prostate cancer (NEPC) is the aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% lethal CRPC. The mechanisms underlying the progression of PCa to NEPC are still largely unclear, and new drug targets are desperately needed. NEPC is highly vascularized (angiogenic) and characterized by high expression of neuroendocrine markers. However, direct molecular links connecting angiogenesis and neuroendocrine differentiation are elusive.

Since epigenetic regulation has been implicated in NEPC progression, we examined expression patterns of 147 epigenetic regulators in primary PCa and NEPC. We found that histone deacetylase 2 (HDAC2) is one of the most upregulated epigenetic regulators in NE tumors compared to non-NE tumors patient prostate tumors. We also found that G-protein coupled receptor kinase 3 (GRK3) is a critical regulator of both angiogenesis and neuroendocrine differentiation. GRK3 expression is pronouncedly elevated in NEPC tumors from GEM models and patients. GRK3 downregulates REST (the master repressor of neuronal genes) and TSP1 (a potent anti-angiogenic factor). Therefore, GRK3 is the key molecular link between angiogenesis and neuroendocrine differentiation. Interestingly, GRK3 phosphorylates HDAC2, which binds to the promoters of REST and TSP1 to repress their expression in PCa cells. We further validated GRK3 as a suitable drug target using our novel GRK3 inhibitor in NEPC cells in culture and in vivo. Our GRK3 inhibitor significantly inhibited the growth of xenograft tumors and substantially reduced HDAC2 phosphorylation and NE markers expression. In summary, our results have expanded our knowledge of PCa progression and provided substantial evidence to nominate GRK3 as a valuable drug target for PCa patients.

Keywords

Prostate Cancer, neuroendocrine differentiation, angiogenesis, HDAC2 Histone Deacetylase 2, epigenetic regulation, GRK3 G protein-coupled receptor kinase 3, REST, TSP, androgen deprivation, hypoxia

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