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ΔNp63α is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis Keyes, William M., 1973- Pecoraro, Matteo, 1984- Aranda, Victoria Vernersson Lindahl, Emma Li, Wangzhi Vogel, Hannes Guo, Xuecui Garcia, Elvin L. Michurina, Tatyana V. Enikolopov, Grigori Muthuswamy, Senthil K. Mills, Alea A. 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. We thank Johannes Zuber, Michael Hemann, and Scott Lowe for assistance and advice; Yuri Lazebnik and Dominik Duelli for DMBA-treated tissues; Chris Johns and Sohail Khan for microarray analysis; and Leif Ellisen and James W. Rocco for HNSCC cell lines. W.M.K. was funded by the Spanish Ministry of Science and Innovation (Plan Nacional –SAF2010-18829). A.A.M. was funded by an ACS Research Scholar Award (RSG-06-190-01-MGO). 2020-12-01T08:02:50Z 2020-12-01T08:02:50Z 2011 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Cell Stem Cell. 2011; 8(2):164-76 info:eu-repo/grantAgreement/ES/3PN/SAF2010-18829 © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.stem.2010.12.009 that appeared in the journal Cell stem cell. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: https://www.elsevier.com/about/our-business/policies/open-access-licenses/elsevier-user-license http://www.elsevier.com/open-access/userlicense/1.0/ info:eu-repo/semantics/openAccess Elsevier