Title | Loss of transcription factor KLF5 in the context of p53 ablation drives invasive progression of human squamous cell cancer. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Yang Y, Nakagawa H, Tetreault M-P, Billig J, Victor N, Goyal A, Sepulveda AR, Katz JP |
Journal | Cancer Res |
Volume | 71 |
Issue | 20 |
Pagination | 6475-84 |
Date Published | 2011 Oct 15 |
ISSN | 1538-7445 |
Keywords | Animals, Cell Line, Cell Transformation, Neoplastic, Cells, Cultured, Disease Progression, Esophageal Neoplasms, Esophagus, Fibroblasts, Humans, Keratinocytes, Kruppel-Like Transcription Factors, Mice, Mice, SCID, Mutation, Neoplasm Invasiveness, Neoplasms, Squamous Cell, Receptor, Notch1, Tumor Suppressor Protein p53 |
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. |
DOI | 10.1158/0008-5472.CAN-11-1702 |
Alternate Journal | Cancer Res |
PubMed ID | 21868761 |
PubMed Central ID | PMC3193554 |
Grant List | R01 DK080031-04 / DK / NIDDK NIH HHS / United States P30 DK050306 / DK / NIDDK NIH HHS / United States R01 DK080031 / DK / NIDDK NIH HHS / United States P01 CA098101 / CA / NCI NIH HHS / United States P30 CA016520 / CA / NCI NIH HHS / United States DK080031-02S1 / DK / NIDDK NIH HHS / United States |
Related Faculty:
Abha Goyal, M.D.