LAUSR

Linker histone H1.2 (H1.2), encoded by HIST1H1C (H1C), is a major H1 variant in somatic cells. Among five histone H1 somatic variants, upregulated H1.2 was found in human hepatocellular carcinoma (HCC) samples and in a diethylnitrosamine (DEN) induced HCC mouse model. In vitro, H1.2 overexpression accelerated proliferation of HCC cell lines, while H1.2 knockdown had the opposite effect. In vivo, H1.2 insufficiency or deficiency (H1c KD or H1c KO) alleviated inflammatory response and HCC development in DEN-treated mice. Mechanistically, H1.2 regulated the activation of signal transducer and activator of transcription protein 3 (STAT3), which in turn positively regulated H1.2 expression by binding to its promoter. Moreover, upregulation of H1.2/STAT3 axis was observed in human HCC samples, and was confirmed in mouse models of methionine-choline-deficient diet induced non-alcoholic steatohepatitis or lipopolysaccharide induced acute inflammatory liver injury. Disrupting this feed-forward loop by knockdown of STAT3 or administrating STAT3 inhibitors, rescued H1.2 overexpression induced proliferation. Moreover, STAT3 inhibitor treatment ameliorated H1.2 overexpression promoted xenograft tumor growth. Therefore, H1.2 plays a novel role in inflammatory response via regulating STAT3 activation in HCC, thus, blockade H1.2/STAT3 loop is a potential strategy against HCC.