The Long and Short of a GWAS-Identified Long Non-Coding RNA
Abstract
Cancer is a major burden to the health system. Prostate cancer alone is predicted to cost the Australian economy >$7 billion and the U.S. economy US$16 billion by 2020 in health care costs and compensation. Despite vigorous attempts to improve patient outcome, median survival for advanced disease patients remains low. Therefore, novel approaches to improve patient outcome are a high unmet clinical need. Finding a cure for advanced prostate cancer is an extremely challenging undertaking; however, it is realistically achievable in the short term to mid-term to identify new targets essential to the progression of prostate cancer and to develop innovative targeted therapies that prevent prostate cancer from forming metastases (containment); stop progression of more aggressive, castrate-resistant prostate cancer (stabilization); and have limited side effects (reduce patient suffering). These innovative drugs would be used in combination with current therapies with the ultimate goal of prolonging patient survival. Genome-wide association studies (GWAS), which assess thousands of DNA genetic variations in large groups of men, have provided insight into the genomic regions that alter an individual’s risk of developing this disease. GWAS have shortlisted 160 prostate cancer risk regions or loci (out of 3 billion DNA bases). The critical post-GWAS step is to now undertake in-depth analyses of these 160 loci to identify their function. Understanding the functional role of these prostate cancer risk-associated genetic variants has the potential to provide insights into the mechanisms driving prostate cancer and to identify novel targets for prostate cancer treatment. Most of these genetic variants are enriched in regulatory regions, outside of the protein-coding genes. The functional consequences of the GWAS variants have been mostly analysed on the regulation of protein-coding genes, with the exception of a few studies involving molecules called long non-coding RNAs (lncRNAs). LncRNAs are a large and diverse class of transcribed RNA molecules with a length of more than 200 nucleotides that do not encode proteins and are emerging as an important mediators in cancer progression and potential therapeutic targets for disease management. Our group is leading the analysis of one such GWAS locus at chromosome 5p15, which is associated with prostate cancer risk in multiple ethnicities. Through the genetic association approaches, i.e., by analysing the genomic DNA of >100,000 individuals and high-throughput sequencing approaches, we discovered a novel lncRNA that is overexpressed in prostate tumor samples compared to the adjacent benign tissue. Interestingly, the expression of this lncRNA is correlated with disease aggressiveness and poor progression-free survival in prostate cancer patient samples. The objective of this project is to understand the role of this newly discovered prostate cancer risk-associated lncRNA in prostate cancer aetiology and to develop a novel therapeutic strategy to target this lncRNA to inhibit prostate cancer growth. Our preliminary data using prostate cancer cell-based (in vitro) assays suggest that this lncRNA promotes prostate cancer progression, making it a rational target for prostate cancer treatment. Importantly, this lncRNA might also produce small peptides (<50 amino acids). The mechanism of action of the RNA as an lncRNA or as a small peptide in prostate cancer initiation and development has not been explored. We aim to unravel the mechanism of action of this lncRNA by deciphering the networks altered by using overexpression and knockdown cell models and patient-derived organoid models. Our study will provide impetus for non-coding RNA-based drug-targeted research by furthering our understanding of this multifactorial disease. It is to be noted that, in the past couple of years, ~100 antisense oligonucleotides and 40 RNAi-based therapies have been tested in clinical trials, includi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910343
Entities
People
- Jyotsna Batra
Organizations
- Queensland University of Technology
- United States Army