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

作者：Vuong Linh M; Chellappa Karthikeyani; Dhahbi Joseph M; Deans Jonathan R; Fang Bin; Bolotin Eugene; Titova Nina V; Hoverter Nate P; Spindler Stephen R; Waterman Marian L; Sladek Frances M^*

来源：Molecular and Cellular Biology, 2015, 35(20): 3471-3490.

DOI：10.1128/MCB.00030-15

The nuclear receptor hepatocyte nuclear factor 4 alpha (HNF4 alpha) 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 alpha 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 alpha 2) or P2-driven (HNF4 alpha 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 HNF4a2 acts as a tumor suppressor in the HCT116 tumor xenograft model, HNF4 alpha 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/beta-catenin mediator T-cell factor 4 (TCF4) at CTTTG motifs as well as at AP-1 motifs (TGAXTCA). Protein binding microarrays (PBMs) show that HNF alpha and TCF4 share some but not all binding motifs and that single nucleotide polymorphisms (SNPs) in sites bound by both HNF4 alpha and TCF4 can alter binding affinity in vitro, suggesting that they could play a role in cancer susceptibility in vivo. Thus, the HNF4 alpha isoforms play distinct roles in colon cancer, which could be due to differential interactions with the Wnt/beta-catenin/TCF4 and AP-I pathways.

• 出版日期2015-10