Role of hepatocyte nuclear factor 4α (HNF4α) in cell proliferation and cancer

Abstract

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.

Figure 1

Scheme showing regulation of hepatocyte proliferation by HNF4α. In quiescent hepatocytes, along with stimulating expression of genes involved in hepatic differentiation, HNF4α also suppresses expression of certain promitogenic genes. Loss of HNF4α results in reprograming of the hepatocyte gene expression program leading to dedifferentiation and increased proliferation.

Figure 2

Proposed mechanisms by which HNF4α suppresses hepatocyte proliferation. HNF4α inhibits hepatocyte proliferation via several proposed mechanisms, including direct inhibition of promitogenic genes, inhibition of c-Myc and cyclin D1 function, miRNA regulation, and upregulation of cyclin F.