Title:

Understanding the Epigenetic Role of PRMT5 Inhibitors in RNA Binding Proteins and Histones Involved in Merkel Cell Carcinoma Tumorigenesis

Frequent alternative splicing changes in cancer are emerging as critical signatures for tumor progression and therapy. Here, we suggest that Merkel cell carcinoma (MCC) cells offer unique opportunities for studying alternative splicing in cancer, as virus-positive MCC specimens exhibit substantially lower mutational burdens compared to virus-negative MCC, despite their phenotypic indistinguishability. MCC is a rare but aggressive form of neuroendocrine skin cancer with a 30% mortality rate. Eighty percent occurs due to the integration of Merkel cell polyomavirus (MCPyV) in the human genome, and the rest is caused by excessive exposure to sunlight or ultraviolet light (UV) which leads to UV-induced DNA damage. Many factors are involved in the development of cancer, such as protein arginine methyltransferase 5 (PRMT5) which plays a significant role in controlling the oncogenic process, and therapy response. Therefore, I aim to investigate the roles of PRMT5-mediated epigenetic modifications of RNA binding proteins (RBPs) and histones using Merkel cells. Increased PRMT5 expression in several types of cancer has been found to be a potential target for treatment. Hence, it will be critical to further understand the physiological functions of PRMT5 in MCC which may shed light on combinatorial therapies or dose-limiting in a therapeutic setting which to date is poorly studied.

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