P1 promoter-driven HNF4α isoforms are specifically repressed by β-catenin signaling in colorectal cancer cells

Abstract

HNF4α is a key nuclear receptor for regulating gene expression in the gut. Although both P1 and P2 isoform classes of HNF4α are expressed in colonic epithelium, specific inhibition of P1 isoforms is commonly found in colorectal cancer. Previous studies have suggested that P1 and P2 isoforms might regulate different cellular functions. Despite these advances, it remains unclear whether these isoform classes are functionally divergent in the context of human biology. Here, the consequences of specific inhibition of P1 or P2 isoform expression was measured in a human colorectal cancer cell transcriptome. Results indicate that P1 isoforms were specifically associated with the control of cell metabolism, whereas P2 isoforms globally supported aberrant oncogenic signalization, promoting cancer cell survival and progression. P1 promoter-driven isoform expression was found to be repressed by β-catenin, one of the earliest oncogenic pathways to be activated during colon tumorigenesis. These findings identify a novel cascade by which the expression of P1 isoforms is rapidly shut down in the early stages of colon tumorigenesis, allowing a change in HNF4α-dependent transcriptome, thereby promoting colorectal cancer progression.This article has an associated First Person interview with the first author of the paper.

Human Hepatocyte Nuclear Factor 4-α encodes isoforms with distinct transcriptional functions

“…In conclusion, the present study provides an exhaustive analysis of the transcriptional co-interacting complexes and transcriptomic impact of each single HNF4α isoforms in a specific cellular setting. Given that specificity of biological functions was previously attributed to HNF4α-P1 and -P2 subclasses (Babeu et al, 2018; Chellappa et al, 2016), this work provides a strong rationale to further detail the exact nature of contributing HNF4α isoforms in given biological systems and to design innovative strategies in exploring the specific biological functions that may be coincidental to the expression of these specific isoforms in the biological field. Similar analyses could be designed for the study of other human NR isoforms that result from similar alternative promoter and splicing events.…”

“…Different numbering and identifiers are currently used when referring to the HNF4α isoforms (Supplementary Table 1), and several studies on HNF4α either do not precisely indicate which isoform was used, do not provide the cDNA sequence, or simply refer to a previous study. This has led to contradictory functions being attributed to HNF4α as a consequence of studying different isoforms (Babeu et al, 2018; Chellappa et al, 2016; Vuong et al, 2015). In order to simplify the nomenclature of the isoforms, we now propose to follow the P1 and P2 classification of isoforms, first by sorting the isoforms from the N-termini, and then by the different C-termini as also suggested by (Ko et al, 2019).…”

“…The expression levels of these isoform classes have been modulated in the colon, notably by RNA interference in a colorectal cancer line or by exon exchange in the mouse, in order to analyze the functional differences between P1 and P2. These studies revealed significant disparities, with P1 isoforms being involved in the regulation of cell differentiation and metabolism, whereas P2 isoforms were associated with cell proliferation and cancer progression (Babeu et al, 2018; Chellappa et al, 2016).…”

Human Hepatocyte Nuclear Factor 4-α Encodes Isoforms with Distinct Transcriptional Functions

“…This has led to contradictory functions being attributed to HNF4 as a consequence of studying different isoforms (44)(45)(46). In order to simplify the nomenclature of the isoforms, we now propose to follow the P1 and P2 classification of isoforms, first by sorting the isoforms from the N-termini, and then by the different C-termini as also suggested by (47).…”

“…The expression levels of these isoform classes have been modulated in the colon, notably by RNA interference in a colorectal cancer line or by exon exchange in the mouse, in order to analyze the functional differences between P1 and P2. These studies revealed significant disparities, with P1 isoforms being involved in the regulation of cell differentiation and metabolism, whereas P2 isoforms were associated with cell proliferation and cancer progression (44,46).…”