Studies of Genetic and Epigenetic Determinants of Prostate Cancer

Prostate cancer (PCa) is a complex and heterogeneous disease, and the molecular mechanisms contributing to PCa is poorly understood. This dissertation focuses on the genetic and epigenetic determinants of PCa. In the first study, we showed that miR-101 negatively regulates EZH2, a key epigenetic regulator by causing aberrant methylation of histones in cancer. We also demonstrated that the forced expression of miR-101 reduces the tumorigenicity of PCa cells. These results suggest that miR-101 plays a regulatory role in PCa, and restoring its expression may be an effective therapeutic approach. In the second study, Jianfeng Xu et al. performed an Affymetrix SNP microarray analysis of 78 human PCa tissues to determine the correlation between genetic alteration and PCa occurrence/progression. From their analysis, we focused on chromosome 8p found to be frequently loss in ~60% of human PCa suggesting that this region may harbor tumor suppressor genes. We focused on the transcription factor SOX7 located on 8p24. We demonstrated that ectopic SOX7 inhibited the growth and invasiveness of PCa cells, and its depletion by siRNA endowed tumorigenicity to non-tumorigenic cells. Furthermore, knockdown of SOX7 enhanced the growth, survivability, and migration of normal mouse prostatic epithelial cells. Altogether, these results suggest SOX7 may possess tumor suppressor activity. Finally, in the third study, we showed that the miR-497-195 cluster, found deleted in 70% of PCa as indicated by an Affymetrix SNP microarray (Jianfeng Xu et al.), potentially possesses tumor suppressor activity by targeting Fatty Acid Synthase. Overall, this dissertation provides further insights for the understanding of the mechanisms which underlie PCa initiation and progression.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2011

Author dc:creator

• Cao, Paul D.

• Epigenetic

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/33442

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/33442