p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis.
We demonstrate that deltaNp63alpha is an essential survival factor in head and neck squamous cell carcinoma (HNSCC) through its ability to suppress p73-dependent apoptosis. Inhibition of endogenous p63 expression by RNAi induces apoptosis selectively in HNSCC cells that overexpress deltaNp63alpha. Knockdown of p63 induces the proapoptotic bcl-2 family members Puma and Noxa, and both their induction and subsequent cell death are p53 independent but require transactivating isoforms of p73. Inhibition of p73-dependent transcription by deltaNp63alpha involves both direct promoter binding and physical interaction with p73. In HNSCC cells lacking endogenous deltaNp63alpha expression, bcl-2 is instead upregulated and can suppress p73-mediated death. Together, these data define a pathway whereby deltaNp63alpha promotes survival in squamous epithelial malignancy by repressing a p73-dependent proapoptotic transcriptional program.
Rocco
James W
JW
Massachusetts General Hospital Center for Cancer Research and Harvard Medical School, Boston, Massachusetts 02114, USA.
Leong
Chee-Onn
CO
Kuperwasser
Nicolas
N
DeYoung
Maurice Phillip
MP
Ellisen
Leif W
LW
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D019254:Genes, bcl-2; D016158:Genes, p53; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C498702:PMAIP1 protein, human; D010750:Phosphoproteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins