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

Abstract

Hepatocyte nuclear factor 4 alpha (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 re-expression 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 pro-mitogenic genes, significant crosstalk with other cell cycle regulators including c-Myc and Cyclin D1, and regulation of miRNAs. Furthermore, studies indicate that post-translational 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.

Identifying Signalling Pathways Regulated by GPRC5B in β-Cells by CRISPR-Cas9-Mediated Genome Editing

“…Consistent with the MIN6 β-cell apoptosis data provided here, 3 of the top 4 array pathways (progesterone receptor, TGF-β and IFNγ) are reported to be pro-apoptotic in β-cells [19-21]. In addition, Gprc5b over-expression was associated with up-regulation of the pro-proliferative E2F transcription factor [22] and down-regulation of HN4α, a repressor of proliferation [23], in keeping with our observations of enhanced proliferation following increased Gprc5b expression in MIN6 β-cells.…”

“…In addition to increased signalling through pro-apoptotic pathways, we also identified that Gprc5b couples to signalling via E2F, which is known to promote β-cell proliferation [37, 38], and its down-regulation of HNF4α signalling is consistent with the reported role of this transcription factor as an inhibitor of proliferation [23] and the effects of an HNF4α antagonist to stimulate β-cell proliferation [39]. It is unusual for individual receptors to be coupled to pathways that induce both apoptosis and proliferation, as has been identified here for Gprc5b, but it is possible that enhanced proliferation is required to compensate for the potentially deleterious effects of activation of the pro-apoptotic cascades described above.…”

TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

“…Transcription factor, hepatocyte nuclear factor 4 alpha (HNF4α), is important for maintaining differentiated state and inhibiting proliferation in quiescent liver . Several studies indicate crosstalk between CAR and HNF4α involving direct competition .…”

The role of hepatocyte nuclear factor 4-alpha in perfluorooctanoic acid- and perfluorooctanesulfonic acid-induced hepatocellular dysfunction

“…We conducted an exhaustive microarray and a separate RNA sequencing analysis in wild type and HNF4α -KO mice. The genes that were significantly different (both up and down) were then compared to published ChIP sequencing analysis to identify the genes with HNF4α binding sites upstream of the promoter region in mice (Gunewardena et al, 2015, Walesky et al, 2013a, Walesky et al, 2013b, Walesky and Apte, 2015). Specific filters were used to identify human orthologs, and we confirmed these genes are also targets in humans.…”