The role of protein arginine N-methyltransferase 5 (PRMT5) as an epigenetic modulator in colorectal carcinoma

Protein arginine N-methyltransferase 5 (PRMT5) enzyme is one of 8 canonical PRMTs and is classified as a type II PRMT that induces arginine monomethylation and symmetric dimethylation. Accumulating evidence suggests that PRMT5 is a potential therapeutic target and biomarker for multiple types of cancer including colorectal cancer (CRC). PRMT5 inhibitors are currently undergoing phase I/II clinical trials for solid tumors. However, there is a lack of knowledge regarding the molecular basis of PRMT5 oncogenic effect in CRC. Furthermore, the number of studies that investigated the PRMT5 inhibitor synergistic effect with conventional chemotherapy in CRC remains limited. In this study, first, we aimed at exploring the molecular alterations associated with PRMT5 in CRC progression. Then, to investigate the contribution of PRMT5 in the epigenetic modulation of DKK1 as a key player in CRC. Lastly, to investigate the capacity of PRMT5 inhibitors to enhance the anticancer activity of conventional chemotherapy in CRC. To address the research question, in silico analysis of gene expression of CRC patients along with PRMT5 knocked down CRC cell lines was performed. Q-PCR and Western blot were performed for validation. A ChIP assay was carried out to investigate the relationship between PRMT5 and targeted genes. IC50 and synergy between PRMT5 inhibitor and doxorubicin were assessed using resazurin assay. Our in-silico data revealed a positive relationship between PRMT5 and DKK1. This was confirmed via Q-PCR and Western blot. DKK1 expression was correlated with reduced proliferation of CRC cell lines. Furthermore, our preliminary results show a synergistic effect between CMP5 and doxorubicin. In conclusion, these findings suggest that PRMT5 exerts significant oncogenic effects in CRC and that inhibition of PRMT5 can enhance the therapeutic efficacy of standard chemotherapy by suppressing the expression of key oncogenic genes in CRC. Further work is still needed to better characterize the role of PRMT5 in CRC development and progression.