Functional Analysis of Risk Single Nucleotide Polymorphism and Long Noncoding RNA in Prostate Cancer

Prostate cancer is the most commonly diagnosed non-cutaneous cancer in men worldwide. While most low-risk prostate cancer patients have a favourable clinical outcome, intermediate- and high-risk patients with aggressive forms of the disease often relapse despite the initially effective local and conventional androgen-deprivation therapies. Therefore, two main challenges in the field of prostate cancer are patient stratification into appropriate risk groups through prognostic biomarkers and novel therapeutic options for patients with aggressive prostate cancer. Prostate cancer has a strong genetic component, with Genome-wide Association Studies (GWAS) identifying over 150 risk single nucleotide polymorphisms (SNPs). While these risk SNPs are associated with prostate cancer predisposition and a few also associated with disease progression, their functional mechanisms remain elusive. Here, I evaluated the association of the risk SNP rs11672691 with prostate cancer progression and its clinical relevance, and uncovered its regulatory mechanisms at a novel bifunctional enhancer-promoter element to dysregulate two gene isoforms of a long noncoding RNA (lncRNA) PCAT19. Furthermore, I validated the oncogenic properties of the lncRNA PCAT19, and revealed its function in prostate cancer progression through the upregulation of a subset of cell cycle genes with the RNA binding protein HNRNPAB. My work signifies the clinical importance in understanding the functional mechanisms of prostate cancer risk SNPs and lncRNAs in prostate cancer. Additionally, my work also shed light on the function and molecular mechanisms of a novel class of regulatory elements in the human genome, and its role in cancer aggressiveness.

Department dc:contributor.department

Medical Biophysics

Year dc:date.issued

2019

Author dc:creator

• Hua, Jun Jie

Advisors dc:contributor.advisor

• He, Housheng
• Tsao, Ming-Sound

• Bifunctional promoter-enhancer
• Cancer
• Epigenetics
• Long noncoding RNA
• Prostate Cancer
• Single nucleotide polymorphism

Handle dc:identifier.uri

http://hdl.handle.net/1807/97010

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/97010