Transcriptional activity mediated by beta-CATENIN and TCF/LEF family members is completely dispensable for survival of multiple human colorectal cancer cell lines

Abstract

Unrestrained transcriptional activity of {beta}-CATENIN and its binding partner TCF7L2 frequently underlies colorectal tumor initiation and is considered an obligatory oncogenic driver throughout intestinal carcinogenesis. Yet, the TCF7L2 gene carries inactivating mutations in about 10 % of colorectal tumors and is non-essential in colorectal cancer (CRC) cell lines. To determine whether CRC cells acquire TCF7L2-independence through cancer-specific compensation by other T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) family members, or rather lose addiction to {beta}-CATENIN/TCF7L2-driven gene expression altogether, we generated multiple CRC cell lines entirely negative for TCF/LEF or {beta}-CATENIN expression. Viability of these cells demonstrates complete {beta}-CATENIN- and TCF/LEF-independence, albeit one {beta}-CATENIN-deficient cell line eventually became senescent. Absence of TCF/LEF proteins and {beta}-CATENIN consistently impaired CRC cell proliferation, reminiscent of mitogenic effects of WNT/{beta}-CATENIN signaling in the healthy intestine. Despite this common phenotype, {beta}-CATENIN-deficient cells exhibited highly cell-line-specific gene expression changes with little overlap between {beta}-CATENIN- and TCF7L2-dependent transcriptomes. Apparently, {beta}-CATENIN and TCF7L2 control sizeable fractions of their target genes independently from each other. The observed divergence of {beta}-CATENIN and TCF7L2 transcriptional programs, and the finding that neither {beta}-CATENIN nor TCF/LEF activity is strictly required for CRC cell survival has important implications when evaluating these factors as potential drug targets.