Incompatibility of the circadian protein BMAL1 and HNF4? in hepatocellular carcinoma.

ABSTRACT: Hepatocyte nuclear factor 4 alpha (HNF4?) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4?. This study reveals that P1-HNF4?, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4?, driven by an alternative promoter (P2-HNF4?), is induced in HNF4?-positive human hepatocellular carcinoma (HCC). P2-HNF4? represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4?. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4? in HCC, and demonstrate that forced expression of BMAL1 in HNF4?-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4?-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.

SUBMITTER: Fekry B 

PROVIDER: S-EPMC6195513 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature