Date of Graduation

Summer 8-11-2017

Document Type

Thesis

Degree Name

Master of Science in Biology

College/School

College of Arts and Sciences

Department/Program

Biology

First Advisor

Dr. Christina Tzagarakis-Foster, Ph.D.

Second Advisor

Dr. James Sikes, Ph.D.

Third Advisor

Dr. Mary Jane Niles, Ph.D.

Abstract

DAX-1 (Dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X-chromosome, gene 1) is an unusual member of the Nuclear Hormone Receptor superfamily that has the ability to interact with other Nuclear Receptors (NRs) and transcriptional co-repressors and co-activators. While DAX-1 plays an important role in adrenal and gonadal development, recent studies have elucidated the role DAX-1 plays as a transcriptional repressor and its influence on the progression of different types of cancers. The primary aim of this thesis research project is to investigate the role of non-aromatizable androgens in inducing DAX-1 expression and to determine how DAX-1 influences proliferation, apoptosis, and metastasis in prostate cancer cells. Using a non-aromatizable androgen, we were able to analyze DAX-1 expression in Androgen Receptor (AR) positive and negative prostate cancer cell lines. We also performed chromatin immunoprecipitation to ascertain if the AR protein plays a role in the transcriptional regulation of the DAX-1 gene. Through these assays, we were able to analyze the link between AR and DAX-1 expression in the context of prostate cancer. In an attempt to understand how AR and DAX-1 influence proliferation, apoptosis, and metastasis in prostate cancer cells, we analyzed different target genes involved in these pathways as well as their effects in proliferation, apoptosis, and metastasis rates after treatment with a non-aromatizable androgen. Transient transfections of DAX-1 and CRISPR-Cas9 knock out of DAX-1were used to understand the effects of DAX-1 in regulating proliferation, apoptosis, and metastasis. Results showed that DAX-1 plays a central role in regulating genes pivotal for proliferation, apoptosis, and metastasis in prostate cancer cells. These results exposed the complexity of cancer biology in prostate cancer cell progression, as well as a deeper understanding of how transcriptional repressors such as DAX-1 can influence the progression of certain types of cancers.

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