Hepatocellular Protein Arginine Methyltransferase 1 Suppresses Alcohol‐Induced Hepatocellular Carcinoma Formation by Inhibition of Inducible Nitric Oxide Synthase

Abstract

Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which alcohol promotes liver cancer are not well understood. Studies suggest that ethanol may enhance tumor progression by increasing hepatocyte proliferation and through alcohol-induced liver inflammation. Protein arginine methyltransferase 1 (PRMT1) is the main enzyme responsible for cellular arginine methylation. Asymmetric dimethyl arginine, produced by PRMT1, is a potent inhibitor of nitric oxide synthases. PRMT1 is implicated in the development of several types of tumors and cardiovascular disease. Our previous work has shown that PRMT1 in the liver regulates hepatocyte proliferation and oxidative stress and protects from alcohol-induced liver injury. However, its role in HCC development remains controversial. In this study, we found that hepatocyte-specific PRMT1-knockout mice develop an increased number of tumors in an N-nitrosodiethylamine (DEN) alcohol model of liver tumorigenesis in mice. This effect was specific to the alcohol-related component because wild-type and knockout mice developed similar tumor numbers in the DEN model without the addition of alcohol. We found that in the presence of alcohol, the increase in tumor number was associated with increased proliferation in liver and tumor, increased WNT/β-catenin signaling, and increased inflammation. We hypothesized that increased inflammation was due to increased oxidative and nitrosative stress in knockout mice. By blocking excess nitric oxide production using an inducible nitric oxide synthase inhibitor, we reduced hepatocyte death and inflammation in the liver and prevented the increase in WNT/β-catenin signaling, proliferation, and tumor number in livers of knockout mice. Conclusion: PRMT1 is an important protection factor from alcohol-induced liver injury, inflammation, and HCC development. (Hepatology Communications 2020;4:790-808). SEE EDITORIAL ON PAGE 787H epatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. (1,2) Unlike other cancers with known risk factors, molecular mechanisms of HCC development are not completely understood. Most patients with HCC have a history of chronic liver disease and cirrhosis, (3) but cirrhosis associated with hepatitis B and C and chronic alcohol drinking account for most cases. (4) About 40% of individuals who chronically consume alcohol develop fatty liver, which can advance to alcoholic hepatitis and/or cirrhosis. Although there have been conflicting findings, currently it is accepted that

Hepatic PRMT1 ameliorates diet-induced hepatic steatosis via induction of PGC1α

“…Given that the amino acid sequences of human and mouse PRMT1 proteins share 99% identity and the expression level of PRMT1 and PGC-1α negatively correlated with liver fat content are conserved between human and mouse, we expect the underlying regulatory mechanism is similar. Interestingly, recent studies reported that PRMT1 could protect alcohol-induced liver injury and suppress alcohol‐induced hepatocellular carcinoma formation in mice 25 , 26 . We also observed that the expression level of the liver injury markers ALT and AST were higher in obese humans with low hepatic PRMT1 expression ( Table S1 , P = 0.07 for ALT and P = 0.08 for AST).…”

“…It is a paradox that recent studies reported the protective effects of hepatic PRMT1 in alcohol-induced inflammation 25 and hepatocellular carcinoma 26 . The potential side effects of targeting hepatic PRMT1 on liver remain largely unknown.…”

Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

“…Increased expression of PRMT1 has been implicated in the tumorigenesis of multiple cancers including progesterone receptor positive breast cancer, hepatocellular carcinoma (HCC), neuroblastoma, and pancreatic cancer [ 35 , 36 , 37 , 38 ]. PRMT1 is also a known contributor to the development of glioblastoma (GBM) [ 15 , 39 ].…”

Protein arginine methyltransferases and hepatocellular carcinoma: A review

“…Several previous studies have revealed the roles that PRMTs play in HCC. PRMT1 inhibition results in reduced HNF4α expression and hepatocyte proliferation, thus promoting alcohol-induced HCC progression, which suggests that PRMT1 seems to perform a protective role in the context of alcohol-induced HCC [ 52 , 53 , 31] . Nevertheless, PRMT1 functions as an oncogene in other contexts of HCC.…”