Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma

Identifier:  imarina:6389520

Handle: https://hdl.handle.net/20.500.11797/imarina6389520

Authors:  Fekry B; Ribas-Latre A; Baumgartner C; Deans J; Kwok C; Patel P; Fu L; Berdeaux R; Sun K; Kolonin M; Wang S; Yoo S; Sladek F; Eckel-Mahan K

Abstract:
© 2018, The Author(s). Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4α. This study reveals that P1-HNF4α, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4α, driven by an alternative promoter (P2-HNF4α), is induced in HNF4α-positive human hepatocellular carcinoma (HCC). P2-HNF4α represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4α. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4α in HCC, and demonstrate that forced expression of BMAL1 in HNF4α-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4α-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.