SATB2 augments ΔNp63α in head and neck squamous cell carcinoma.
ΔNp63α is a critical pro-survival protein overexpressed in 80% of head and neck squamous cell carcinomas (HNSCCs) where it inhibits TAp73β transcription of p53-family target genes, which is thought to increase HNSCC resistance to chemotherapy-induced cell death. However, the mechanisms governing ΔNp63α function are largely unknown. In this study, we identify special AT-rich-binding protein 2 (SATB2) as a new ΔNp63α-binding protein that is preferentially expressed in advanced-stage primary HNSCC and show that SATB2 promotes chemoresistance by enhancing ΔNp63α-mediated transrepression by augmenting ΔNp63α engagement to p53-family responsive elements. Furthermore, SATB2 expression positively correlates with HNSCC chemoresistance, and RNA interference-mediated knockdown of endogenous SATB2 re-sensitizes HNSCC cells to chemotherapy- and γ-irradiation-induced apoptosis, irrespective of p53 status. These findings unveil SATB2 as a pivotal modulator of ΔNp63α that governs HNSCC cell survival.
Chung
Jacky
J
Department of Molecular Genetics, University of Toronto, Cell Biology Program, Hospital for Sick Children Research Institute, Department of Paediatrics, 555 University Avenue, Toronto, Ontario, M5G 1L7, Canada.
Lau
Joanne
J
Cheng
Lynn S
LS
Grant
R Ian
RI
Robinson
Fiona
F
Ketela
Troy
T
Reis
Patricia P
PP
Roche
Olga
O
Kamel-Reid
Suzanne
S
Moffat
Jason
J
Ohh
Michael
M
Perez-Ordonez
Bayardo
B
Kaplan
David R
DR
Irwin
Meredith S
MS
D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D036961:Matrix Attachment Region Binding Proteins; C521297:SATB2 protein, human; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins