The Role of Alternative Polyadenylation in Advanced Prostate Cancer
Abstract
Current approaches that apply gene expression analyses to study prostate cancer biology, or to provide personalized treatment, are significantly limited. The problem lies in the fact that gene expression levels do not always equate with gene activity. Specifically, for more than half of genes measured in gene expression analyses, the levels of proteins (the downstream product of most genes) do not equate with the level of gene transcript (mRNA, the entity measured in gene expression analysis). Thus, a gene might be considered "on" from gene expression results, but it is actually "off" at the protein level. This can mislead scientists studying prostate cancer biology or clinicians who are trying to determine how to best treat a patient. This problem arises from our poor understanding of post-transcriptional modifications, where gene transcripts (mRNA) can be modified before they are used to guide protein synthesis and gene activity. Here we propose comprehensive analyses of a highly important post-transcriptional regulatory pathway, mRNA Polyadenylation, for its importance in prostate cancer biology and in the treatment of prostate cancer. Upon successful completion of these studies, these efforts will improve the ability of others to predict protein expression and cancer biology (aggressive or nonaggressive) from gene expression data, uncover new mechanisms of gene regulation that could be targeted for therapy, and uncover new pathways that could be useful for determining cancer aggressiveness or susceptibility to certain therapies. Here we propose three specific aims to study how mRNA polyadenylation, at different sites along a gene, determines prostate cancer biology, aggressiveness, and gene expression. Aim 1: To define the variation of polyadenylation site selection in human prostate cancer and its relationship with disease phenotype, miRNA expression, and 3´UTR regulatory elements. These studies will provide a genome-wide map of where gene transcripts are polyadenylated in prostate cancer. They will determine if different polyadenylation patterns are associated with specific clinical phenotypes, such as a cancer that is more likely to recur. They will further determine how different polyadenylation patterns affect gene expression, through microRNA regulatory pathways (microRNAs are genes that bind mRNA transcripts and turn them off). Successful completion of this aim could rapidly impact patients by providing new knowledge regarding gene expression patterns and clinical features, which could be readily incorporated into current gene expression techniques used to assess patient characteristics. These results also have potential for long-term impact by identifying new pathways and regulatory mechanisms associated with cancer aggressiveness or progression. Aim 2: To determine the impact of APA on gene expression and miRNA gene regulation in PCa and castration-resistant prostate cancer (CRPC). These studies are similar in nature to those proposed in Aim 1, except they apply polyadenylation analyses to cancer cells grown in tissue culture dishes. This is important because it will allow detailed biologic analyses of this pathway in living cancer cells. For example, we can turn on or off a specific gene (or microRNA) and then observe if the predicted change in protein expression occurs. Thus, this approach allows for mechanistic analyses that cannot be studied in human tissues. Further, these studies are different because they focus on CRPC. Therefore, new pathways that are relevant to more aggressive and lethal disease will be studied in Aim 2. Aim 3: To determine the impact of polyadenylation regulatory gene activity on CRPC gene expression and phenotype. These studies are focused on mechanism and the important question of whether specific genes that regulate mRNA polyadenylation site selection contribute to prostate cancer aggressiveness. Successful completion of these studies will qualify
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710581
Entities
People
- Shawn E Lupold
Organizations
- Johns Hopkins University
- United States Army