Np63A Up-Regulates the Hsp70 Gene in Human Cancer

HSP70, a stress response protein, is known to be a determinant of cell death and cell transformation. We show that different isoforms of p63 have different transcriptional activities on hsp70 genes. Np63A, an abundantly expressed isoform of p63 , activates (in vitro and in vivo), whereas TAp63; down-regulates the expression of hsp70 . We further show that the transactivation domain at the NH2 terminus of p63 represses, whereas the COOH terminus activates hsp70 transcription. In addition, Np63A regulates transcription of the hsp70 gene through its interaction with the CCAAT binding factor and NF-Y transcription factors which are known to form a complex with the CCAAT box located in the hsp70 promoter. Moreover, Np63A expression correlates with HSP70 expression in all head and neck cancer cell lines. Finally, we show colocalization of Np63A and HSP70 in the epithelium and coexpression of both proteins in 41 primary head and neck cancers. Our study provides strong evidence for the physiologic association between Np63A and hsp70 in human cancer, thus further supporting the oncogenic potential of Np63A. (Cancer Res 2005; 65(3): 758-66)