Loss of transcription factor KLF5 in the context of p53 ablation drives invasive progression of human squamous cell cancer

Yizeng Yang, Hiroshi Nakagawa, Marie Pier Tetreault, Janelle Billig, Noel Victor, Abha Goyal, Antonia R. Sepulveda, Jonathan P. Katz*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Squamous cell cancers account for more than half of all human cancers, and esophageal cancer is the sixth leading cause of cancer death worldwide. The majority of esophageal squamous cell carcinomas have identifiable p53 mutations, yet the same p53 mutations are found at comparable frequencies in precancerous dysplasia, indicating that transformation requires additional somatic changes yet to be defined. Here, we show that the zinc finger transcription factor Krüppel-like factor 5 (KLF5) transactivates NOTCH1 in the context of p53 mutation or loss. KLF5 loss limited NOTCH1 activity and was sufficient on its own to transform primary human keratinocytes harboring mutant p53, leading to the formation of invasive tumors. Restoration of NOTCH1 blocked transformation of KLF5-deficient and p53-mutant keratinocytes. Although human dysplastic epithelia accumulated KLF5, KLF5 expression was lost concurrently with NOTCH1 in squamous cell cancers. Taken together, these results define KLF5 loss as a critical event in squamous cell transformation and invasion. Our findings suggest that KLF5 may be a useful diagnostic and therapeutic target in esophageal squamous carcinomas and possibly more generally in other cancers associated with p53 loss of function.

Original languageEnglish (US)
Pages (from-to)6475-6484
Number of pages10
JournalCancer Research
Volume71
Issue number20
DOIs
StatePublished - Oct 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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