Dominant negative (ΔN) p63α induces drug resistance in hepatocellular carcinoma by interference with apoptosis signaling pathways

p63 belongs to the family of p53-related transcription factors expressing a variety of isoforms. The Trp63 gene has two promoters that drive the expression of two major p63 isoform subfamilies. Isoforms of the TAp63 subfamily show pro-apoptotic activities, whereas members of the N-terminally truncated (Delta N) p63 subfamily have anti-apoptotic functions. We have previously shown an important role for TAp63 alpha. in the induction of apoptosis and chemosensitivity of hepatocellular carcinoma (HCC). Here, we investigated the molecular mechanisms accounting for the oncogenic role of Delta Np63 alpha in HCC. Delta Np63 alpha can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) Delta Np63 alpha of the p53 family and consequently inhibit transactivation of pro-apoptotic target genes. Delta Np63 alpha negatively regulates the genes encoding for the death receptor CD95 and the pro-apoptotic BcI-2 family member BAX. Thus, Delta Np63 alpha a. expression in HCC interferes with both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. In addition and of clinical relevance, Delta Np63 alpha inhibits activation of p53 family target genes and apoptosis induced by chemotherapeutic drugs. Chemotherapeutic treatment induces expression of Bax, Bim, Noxa, Puma and Perp: this is antagonized by Delta Np63 alpha. Our data suggest that the Delta Np63 alpha isoform represses apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways, thereby contributing to chemoresistance of HCC. (C) 2010 Elsevier Inc. All rights reserved.