Dominant negative (DeltaN) p63alpha 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 (DeltaN) p63 subfamily have anti-apoptotic functions. We have previously shown an important role for TAp63alpha in the induction of apoptosis and chemosensitivity of hepatocellular carcinoma (HCC). Here, we investigated the molecular mechanisms accounting for the oncogenic role of DeltaNp63alpha in HCC. DeltaNp63alpha can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of pro-apoptotic target genes. DeltaNp63alpha negatively regulates the genes encoding for the death receptor CD95 and the pro-apoptotic Bcl-2 family member BAX. Thus, DeltaNp63alpha expression in HCC interferes with both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. In addition and of clinical relevance, DeltaNp63alpha 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 DeltaNp63alpha. Our data suggest that the DeltaNp63alpha isoform represses apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways, thereby contributing to chemoresistance of HCC.
Mundt
Heiko M
HM
Department of Internal Medicine IV, University Hospital, Heidelberg, Germany.
Stremmel
Wolfgang
W
Melino
Gerry
G
Krammer
Peter H
PH
Schilling
Tobias
T
Müller
Martina
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins