Differential Effects of Hepatocyte Nuclear Factor 4? Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells.

ABSTRACT: The nuclear receptor hepatocyte nuclear factor 4? (HNF4?) is tumor suppressive in the liver but amplified in colon cancer, suggesting that it also might be oncogenic. To investigate whether this discrepancy is due to different HNF4? isoforms derived from its two promoters (P1 and P2), we generated Tet-On-inducible human colon cancer (HCT116) cell lines that express either the P1-driven (HNF4?2) or P2-driven (HNF4?8) isoform and analyzed them for tumor growth and global changes in gene expression (transcriptome sequencing [RNA-seq] and chromatin immunoprecipitation sequencing [ChIP-seq]). The results show that while HNF4?2 acts as a tumor suppressor in the HCT116 tumor xenograft model, HNF4?8 does not. Each isoform regulates the expression of distinct sets of genes and recruits, colocalizes, and competes in a distinct fashion with the Wnt/?-catenin mediator T-cell factor 4 (TCF4) at CTTTG motifs as well as at AP-1 motifs (TGAXTCA). Protein binding microarrays (PBMs) show that HNF4? and TCF4 share some but not all binding motifs and that single nucleotide polymorphisms (SNPs) in sites bound by both HNF4? and TCF4 can alter binding affinity in vitro, suggesting that they could play a role in cancer susceptibility in vivo. Thus, the HNF4? isoforms play distinct roles in colon cancer, which could be due to differential interactions with the Wnt/?-catenin/TCF4 and AP-1 pathways.

SUBMITTER: Vuong LM 

PROVIDER: S-EPMC4573706 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature