| First Author | Fekry B | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 4349 |
| PubMed ID | 30341289 | Mgi Jnum | J:267959 |
| Mgi Id | MGI:6267946 | Doi | 10.1038/s41467-018-06648-6 |
| Citation | Fekry B, et al. (2018) Incompatibility of the circadian protein BMAL1 and HNF4alpha in hepatocellular carcinoma. Nat Commun 9(1):4349 |
| abstractText | Hepatocyte nuclear factor 4 alpha (HNF4alpha) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4alpha. This study reveals that P1-HNF4alpha, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4alpha, driven by an alternative promoter (P2-HNF4alpha), is induced in HNF4alpha-positive human hepatocellular carcinoma (HCC). P2-HNF4alpha represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4alpha. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4alpha in HCC, and demonstrate that forced expression of BMAL1 in HNF4alpha-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4alpha-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver. |
