Year: 2018
Type: article
Abstract: 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.
Source: Nature Communications
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, American Cancer Society, McGovern Medical School, National Institutes of Health, University of Texas Health Science Center at San Antonio, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1147702603, G1213047067, G1339984560, G1523048982, G1835006133, G2052727244, G2419047272, (PQ6)Nuclear receptor mechanisms in circadian disruption induced hepatocarcinogenesis, Dichotomous Effects of MT1-MMP on Adipose Tissue Remodeling, Origins of Diet-Induced Circadian Reprogramming and Plasticity, Regulation of glucose utilization by skeletal muscle SIK1, G4008938250, G4318476201, G5631262096, G632518272, G6476294849, G6546952425, G8089694902, G9000059699, G9000347126
OpenAlex ID: W2897301109