Cell Stem Cell
Volume 8, Issue 2, 4 February 2011, Pages 164-176
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Article
ΔNp63α Is an Oncogene that Targets Chromatin Remodeler Lsh to Drive Skin Stem Cell Proliferation and Tumorigenesis

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Summary

The p53 homolog p63 is essential for development, yet its role in cancer is not clear. We discovered that p63 deficiency evokes the tumor-suppressive mechanism of cellular senescence, causing a striking absence of stratified epithelia such as the skin. Here we identify the predominant p63 isoform, ΔNp63α, as a protein that bypasses oncogene-induced senescence to drive tumorigenesis in vivo. Interestingly, bypass of senescence promotes stem-like proliferation and maintains survival of the keratin 15-positive stem cell population. Furthermore, we identify the chromatin-remodeling protein Lsh as a new target of ΔNp63α that is an essential mediator of senescence bypass. These findings indicate that ΔNp63α is an oncogene that cooperates with Ras to promote tumor-initiating stem-like proliferation and suggest that Lsh-mediated chromatin-remodeling events are critical to this process.

Highlights

► ΔNp63α, the predominant p63 isoform in skin, overcomes senescence induced by Ras ► Ras and ΔNp63α maintains survival and proliferation of epithelial stem cells ► ΔNp63α cooperates with Ras to cause squamous cell carcinoma in mice ► The chromatin remodeler Lsh is a p63 target required to bypass senescence

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Present address: Centre for Genomic Regulation (CRG), UPF, Barcelona, 08003, Spain