A Novel Role for EZH2 in A-to-I RNA Editing in Prostate Cancer

PI: Qi Cao, PhD, associate professor of Urology 

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.  

Prostate cancer can be caused at genetic and epigenetic levels. Not only do epigenetic modifications include unwinding of genes (i.e., DNA) so they can be expressed as RNA, but this epigenetic regulation can also edit RNA. One epigenetic modifier is protein enzyme enhancer of zest homolog 2 (EZH2) that normally modifies the histone H3K27, 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, which 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 expression levels of EZH2 and ADAR compared to those in benign prostate epithelial cells and 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 edit the substrates in prostate cancer. Next, we will study how EZH2 and ADAR work together to promote prostate cancer progression. 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. 

Read more about this project.