Friday, May 16, 2025
5/16/2025
Combinational targeting histone and RNA modifications in 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. 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 N6-methyladenosine (m6A), which is totally different from its well-known canonical function as a histone lysine methyltransferase. mRNA methylation can affect the stability of RNA and induce alternative splicing of mRNA, which will alter important regulation of the RNA and protein translation fidelity. These aberrant effects on RNA by alterations in RNA modifications are associated with cancer, in particular, prostate cancer. Therefore, investigating this novel EZH2 non-canonical function in N6-methyladenosine 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 been 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 enhances global m6A modification levels via activating m6A reader YTHDF1, enhancing m6A writers METTL14/WTAP protein synthesis, and inducing tumor suppressor mRNA degradation. Most advanced prostate cancer cells have higher expression levels of EZH2 and m6A compared to those in benign prostate epithelial cells and early-stage prostate cancer cells, suggesting the importance of EZH2 and m6A in prostate cancer progression. In the proposed project, we will precisely identify how EZH2 regulates m6A via its non- canonical role in prostate cancer. Understanding these mechanisms will lead to the future design of new inhibitors of EZH2 and m6A writers/readers. Therefore, our work provides a novel rationale to target both METTL3 and EZH2, and we predict that the inhibition of both m6A and EZH2 will achieve a better therapeutic efficacy than inhibiting either m6A or EZH2 alone.
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