The Role of A-to-I RNA Editing in Advanced Prostate Cancer
Abstract
Prostate cancer is one of the most common cancers among men, and although it can successfully be treated in some men, others develop resistance to therapies and can relapse. Thus, it is prudent to discover new therapeutic targets and develop therapeutic strategies that utilize already developed therapies to expedite the development of new treatment options for prostate cancer patients. This proposal will address the overarching challenges of (1) developing treatments that improve outcomes for men with lethal prostate cancer and (2) defining the biology of lethal prostate cancer to reduce death. Prostate cancer can be caused, at least in part, by mutations in genes (e.g., oncogenes and tumor suppressor genes) that can be inherited or acquired over a man’s lifetime, and as a man ages, environmental factors can lead to epigenetic modifications of these genes that can turn the silenced oncogenes “on” and the operating tumor suppressor genes “off.” Not only do epigenetic modifications include unwinding of genes (i.e., DNA), they can be expressed as RNA; but this epigenetic regulation can also edit RNA. One epigenetic modifier is a protein enzyme enhancer of zest homolog 2 (EZH2) that normally modifies the histone H3 protein at its lysine 27, thereby tightly winding DNA and silencing gene expression. Our previous work showed that EZH2 is upregulated in advanced prostate carcinomas and metastatic prostate cancer, and prostate cancer patients who have higher expression levels of EZH2 have shorter survival times than prostate cancer patients with low or no expression of EZH2. Surprisingly, we recently discovered that dysregulation of EZH2 alters RNA editing, which is totally different from its well-known canonical function as a protein modifier. RNA editing can affect the stability of RNA and induce variations, mutations, and truncations in the RNA that alter important regulation of the RNA and protein translation fidelity. These aberrant effects on RNA by alterations in RNA editing are associated with cancer, in particular, prostate cancer. Therefore, investigating this novel EZH2 non-canonical function in RNA editing will help us better understand the progression of advanced prostate cancer. Although the development of EZH2 inhibitors has been an active area of investigation, and multiple biotech and pharmaceutical companies have been developing such drugs, EZH2 inhibitors alone have not proven effective in most solid cancers. Thus, identifying new therapeutics targets will lead to the development of new drugs that can be combined with already developed drugs, hence expediting the development of new treatment options for cancer. Our data show, for the first time, that EZH2 directly interacts with ADAR, which is an RNA-specific adenosine deaminase and one of two enzymes responsible for editing and converting adenosine to inosine in RNA. Most advanced prostate cancer cells have higher levels of EZH2 and ADAR proteins compared to those in early-stage prostate cancer cells, suggesting the importance of both of these proteins in prostate cancer progression. In the proposed project, we will identify precisely how EZH2 and ADAR interact and how these two proteins regulate each other in prostate cancer. Next, we will study how EZH2 and ADAR work together to decrease the expression of tumor suppressors (genes/proteins that inhibit tumor growth) and increase genetic instability in advanced prostate cancer. Understanding these mechanisms will lead to the future design of new inhibitors of EZH2 and ADAR. Therefore, our work provides a novel rationale to target both ADAR and EZH2, and we predict that the inhibition of both ADAR and EZH2 will kill more cancer cells than inhibiting either ADAR or EZH2 alone. Thus far, there is no ADAR-specific inhibitor available, and our study will confirm that ADAR is a viable target, which will instigate biotech and pharmaceutical companies to develop ADAR-specific inhibitors for the treat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910563
Entities
People
- Qi Cao
Organizations
- Northwestern University
- United States Army