A genome-wide RNAi screen for Wnt/β-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer

Wei Tang, Michael Dodge, Deepika Gundapaneni, Carolyn Michnoff, Michael Roth, Lawrence Lum

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

The Wnt family of secreted proteins coordinate cell fate decision-making in a broad range of developmental and homeostatic contexts. Corruption of Wnt signal transduction pathways frequently results in degenerative diseases and cancer. We have used an iterative genome-wide screening strategy that employs multiple nonredundant RNAi reagents to identify mammalian genes that participate in Wnt/β-catenin pathway response. Among the genes that were assigned high confidence scores are two members of the TCF/LEF family of DNA-binding proteins that control the transcriptional output of the pathway. Surprisingly, we found that the presumed cancer-promoting gene TCF7L2 functions instead as a transcriptional repressor that restricts colorectal cancer (CRC) cell growth. Mutations in TCF7L2 identified from cancer genome sequencing efforts abolish its ability to function as a transcriptional regulator and result in increased CRC cell growth. We describe a growth-promoting transcriptional program that is likely activated in CRC tumors with compromised TCF7L2 function. Taken together, the results from our screen and studies focused on members of the TCF/LEF gene family refine our understanding of how aberrant Wnt pathway activation sustains CRC growth.

Original languageEnglish (US)
Pages (from-to)9697-9702
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number28
DOIs
StatePublished - Jul 15 2008

Keywords

  • Cancer genome sequencing
  • Colorectal cancer
  • Functional genomics
  • TCF/LEF transcription factors
  • Wnt signal transduction

ASJC Scopus subject areas

  • General

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