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Open Access Role of Hepatocyte Nuclear Factor 4α (HNF4α) in Cell Proliferation and Cancer

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Hepatocyte nuclear factor 4α (HNF4α) is an orphan nuclear receptor commonly known as the master regulator of hepatic differentiation, owing to the large number of hepatocyte-specific genes it regulates. Whereas the role of HNF4α in hepatocyte differentiation is well recognized and extensively studied, its role in regulation of cell proliferation is relatively less known. Recent studies have revealed that HNF4α inhibits proliferation not only of hepatocytes but also cells in colon and kidney. Further, a growing number of studies have demonstrated that inhibition or loss of HNF4α promotes tumorigenesis in the liver and colon, and reexpression of HNF4α results in decreased cancer growth. Studies using tissue-specific conditional knockout mice, knock-in studies, and combinatorial bioinformatics of RNA/ChIP-sequencing data indicate that the mechanisms of HNF4α-mediated inhibition of cell proliferation are multifold, involving epigenetic repression of promitogenic genes, significant cross talk with other cell cycle regulators including c-Myc and cyclin D1, and regulation of miRNAs. Furthermore, studies indicate that posttranslational modifications of HNF4α may change its activity and may be at the core of its dual role as a differentiation factor and repressor of proliferation. This review summarizes recent findings on the role of HNF4α in cell proliferation and highlights the newly understood function of this old receptor.
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Keywords: Diethylnitrosamine; Hepatocellular carcinoma (HCC); Hepatocytes; Proliferating cell nuclear antigen (PCNA); c-Myc

Document Type: Research Article

Affiliations: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA

Publication date: February 20, 2015

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  • Gene Expression, The Journal of Liver Research will publish articles in all aspects of hepatology. Hepatology, as a research discipline, has seen unprecedented growth especially in the cellular and molecular mechanisms of hepatic health and disease, which continues to have a major impact on understanding liver development, stem cells, carcinogenesis, tissue engineering, injury, repair, regeneration, immunology, metabolism, fibrosis, and transplantation. Continued research and improved understanding in these areas will have a meaningful impact on liver disease prevention, diagnosis, and treatment. The existing journal Gene Expression has expanded its focus to become Gene Expression, The Journal of Liver Research to meet this growing demand. In its revised and expanded scope, the journal will publish high-impact original articles, reviews, short but complete articles, and special articles (editorials, commentaries, opinions) on all aspects of hepatology, making it a unique and invaluable resource for readers interested in this field. The expanded team, led by an Editor-in-Chief who is uniquely qualified and a renowned expert, along with a dynamic and functional editorial board, is determined to make this a premier journal in the field of hepatology.
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