MYC-Protein Arginine Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the MYC oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop new therapies for MYC-driven HCC. Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosoamine (DEN). Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in a MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from HCC patients. Mechanistically, Prmt5, encoding protein arginine methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited anti-proliferative activity via upregulation of the tumor suppressor gene Cdkn1b/p27. In addition, GSK3326595 induced lymphocyte infiltration and MHC II expression, which might contribute to the enhanced anti-tumor immune response. Combination of GSK3326595 with anti-PD-1 immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC. This study revealed that PRMT5 is an epigenetic executer of MYC leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC via PRMT5 inhibition through synergistically suppressed proliferation and enhanced anti-tumor immunity, and finally provides an opportunity to mitigate the resistance of "immune-cold" tumor to ICT.