Human hepatocellular carcinoma(HCC)occurs almost exclusively in cirrhotic livers.Here,we report that hepatic loss of protein arginine methyltransferase 5(PRMT5)in mice is sufficient to cause cirrhosis and HCC in a cli...Human hepatocellular carcinoma(HCC)occurs almost exclusively in cirrhotic livers.Here,we report that hepatic loss of protein arginine methyltransferase 5(PRMT5)in mice is sufficient to cause cirrhosis and HCC in a clinically relevant way.Furthermore,pathological polyploidization induced by hepatic loss of PRMT5 promotes liver cirrhosis and hepatic tumorigenesis in aged liver.The loss of PRMT5 leads to hyperaccumulation of P21 and endoreplication-dependent formation of pathological mono-nuclear polyploid hepatocytes.PRMT5 and symmetric dimethylation at histone H4 arginine 3(H4R3me2s)directly associate with chromatin of P21 to suppress its transcription.More importantly,loss of P21 rescues the pathological mono-nuclear polyploidy and prevents PRMT5-deficiency-induced liver cirrhosis and HCC.Thus,our results indicate that PRMT5-mediated symmetric dimethylation at histone H4 arginine 3(H4R3me2s)is crucial for preventing pathological polyploidization,liver cirrhosis and tumorigenesis in mouse liver.展开更多
基金financially supported by grants from the National Key R&D Program of China(2022YFC3600202,2018YFA0800902)the National Natural Science Foundation of China(31730051,32170834).
文摘Human hepatocellular carcinoma(HCC)occurs almost exclusively in cirrhotic livers.Here,we report that hepatic loss of protein arginine methyltransferase 5(PRMT5)in mice is sufficient to cause cirrhosis and HCC in a clinically relevant way.Furthermore,pathological polyploidization induced by hepatic loss of PRMT5 promotes liver cirrhosis and hepatic tumorigenesis in aged liver.The loss of PRMT5 leads to hyperaccumulation of P21 and endoreplication-dependent formation of pathological mono-nuclear polyploid hepatocytes.PRMT5 and symmetric dimethylation at histone H4 arginine 3(H4R3me2s)directly associate with chromatin of P21 to suppress its transcription.More importantly,loss of P21 rescues the pathological mono-nuclear polyploidy and prevents PRMT5-deficiency-induced liver cirrhosis and HCC.Thus,our results indicate that PRMT5-mediated symmetric dimethylation at histone H4 arginine 3(H4R3me2s)is crucial for preventing pathological polyploidization,liver cirrhosis and tumorigenesis in mouse liver.
