Date of Award

12-1-2012

Degree Type

Dissertation

University or Center

Clark Atlanta University(CAU)

School

School of Arts and Sciences

Degree Name

Ph.D.

Department

Biology

First Advisor

Dr. Jaideep Chaudhary

Second Advisor

Dr. Cimona Hinton

Third Advisor

Dr. Valerie Odero-Marah

Abstract

There are four isoforms of the Inhibitor of DNA-binding/differentiation proteins (Idl-4). Id 1-3 are reportedly overexpressed in various cancer including colorectal, breast, lymphoma and prostate cancer. Id4 is expressed in the normal epithelium of the prostate gland and during early stage prostate cancer, however its expression is lost in advanced stage rnetastatic prostate cancer. In several cancers 1d4 expression is lost through promoter hypermethylation a mechanism cancer cells utilize to silence tumor suppressor genes.. We hypothesized that 1d4 acts as a tumor suppressor in prostate cancer and its expression is downregulated through hypermethylation of the 1d4 promoter. To test this hypothesis, we first observed the methylation status of the 1d4 promoter in both androgen dependent and androgen independent prostate cancer cell lines. Then to observe the significance of 1d4 in prostate cancer, we transfected a full length 1d4 plasmid into the Id4 negative DU14 cell line to observe if 1d4 may act as a tumor suppressor in prostate cancer. Ectopic expression of 1d4 reduced the proliferation rate of the prostate cancer cell line. 1d4 expression resulted in an increase of endogenous apoptosis and an increased sensitivity to apoptotic inducing agents. 1d4 expression initiated senescence at an increased rate of frequency in DU145+1d4 cells. 1d4 inhibited progression of the cell cycle by upregulating key cell cycle regulatory genes p16, p21, p27 SKP2, E2FI. Exogenous 1d4 expression resulted in the expression of a functional androgen receptor that was capable of nuclear translocation in response to androgen treatment and activating the AR target gene PSA. ld4 downregulates the expression of Id I and 1d3, two members of the Id family responsible for increasing prostate cancer progression. These results indicate that Ed4 is a novel tumor suppressor gene in prostate cancer that is responsible for inducing senescence, apoptosis, cell cycle regulation and functional AR activity and that the loss of 1d4 expression in prostate cancer progression is the results of hypermethylation of the 1d4 promoter. 1d4 may be a critical aspect in the transition from androgen dependent prostate cancer to androgen independence. Understanding regulation of the 1d4 gene may provide a crucial target for prostate cancer drug therapy.

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