A Hidden Role of the Inactivated FANCD2: Upregulating ΔNp63

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 Delta Np63 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, Delta Np63 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 Delta Np63 promoter (P2) that can mediate the upregulation of Delta Np63 by an inactivated FANCD2, and determined that elevated Delta Np63 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 Delta Np63 expression in human cancer tissues. Collectively, these results document a novel role of an inactivated FANCD2 in upregulating Delta Np63, advancing our understanding of how an impaired FA pathway contributes to the pathogenesis of human cancer.