A hidden role of the inactivated FANCD2: upregulating ΔNp63.

// Jayabal Panneerselvam 1,* , Anna Pickering 1,* , Jun Zhang 2 , Hong Wang 2,4 , Hui Tian 1,3 , Junnian Zheng 3 , and Peiwen Fei 1 1 University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA 2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 3 Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, China 4 present address: Department of Gastroenterology; First Municipal People’s Hospital of Guangzhou; First Affiliated Hospital Sun Yat-Sen University; Guangzhou, China * These authors equally contributed to this work. Correspondence: Peiwen Fei, email: // Keywords : P63, Fanconi Anemia tumor supressor pathway, oncogene delta N p63, FANCD2, tumorigenicity, transactivation Received : July 29, 2013 Accepted : August 8, 2013 Published : August 11, 2013 Abstract A compromised Fanconi Anemia (FA) signaling pathway, often resulting from an inactivated FANCD2, was recently recognized to contribute to the development of non-FA human tumors. However, it is largely unknown as to how an impaired FA pathway or an inactivated FANCD2 promotes tumorigenesis. Here we unexpectedly found that ΔNp63 mRNA was expressed at high levels in human cancer cells carrying an impaired FA pathway compared to the corresponding control cells carrying an intact FA pathway. This observation was recapitulated upon conditionally managing the status of FANCD2 monoubiquitination /activation in 293T cells. Importantly, ΔNp63 elevation upon FANCD2 inactivation was confirmed in human fibroblasts derived from FA patients. Moreover, we have identified a 189 bp DNA fragment downstream of the ΔNp63 promoter (P2) that can mediate the upregulation of ΔNp63 by an inactivated FANCD2, and determined that elevated ΔNp63 is high enough to promote cancer cell proliferation and metastasis. In vivo , the elevation of FAVL, a tumor promotion factor that inhibits FANCD2 activation, was found to be positively associated with ΔNp63 expression in human cancer tissues. Collectively, these results document a novel role of an inactivated FANCD2 in upregulating ΔNp63, advancing our understanding of how an impaired FA pathway contributes to the pathogenesis of human cancer.