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Establishment of a Clinic-based Biorepository
Published on: May 29, 2017
SATB2 augments ΔNp63α in head and neck squamous cell carcinoma
Jacky Chung1, Joanne Lau, Lynn S Cheng
1Department 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.
Abstract:
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.
Insights
Special AT-rich-binding protein 2 (SATB2) enhances head and neck squamous cell carcinoma (HNSCC) chemoresistance by augmenting ΔNp63α function. Knocking down SATB2 re-sensitizes HNSCC cells to apoptosis, revealing SATB2 as a key survival modulator.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- ΔNp63α is a pro-survival protein overexpressed in head and neck squamous cell carcinomas (HNSCCs).
- ΔNp63α inhibits TAp73β transcription, potentially increasing HNSCC chemoresistance.
- Mechanisms regulating ΔNp63α function in HNSCC remain largely undefined.
Purpose of the Study:
- To identify novel proteins interacting with ΔNp63α.
- To investigate the role of SATB2 in HNSCC chemoresistance and ΔNp63α function.
- To explore SATB2 as a potential therapeutic target in HNSCC.
Main Methods:
- Co-immunoprecipitation to identify ΔNp63α-binding proteins.
- Expression analysis in HNSCC patient samples.
- RNA interference (RNAi) to knockdown SATB2.
- Assessment of apoptosis induction via chemotherapy and γ-irradiation.
Main Results:
- Special AT-rich-binding protein 2 (SATB2) was identified as a novel ΔNp63α-binding protein.
- SATB2 is preferentially expressed in advanced-stage HNSCC.
- SATB2 enhances ΔNp63α-mediated transrepression and promotes chemoresistance.
- SATB2 knockdown re-sensitizes HNSCC cells to chemotherapy and radiation-induced apoptosis.
Conclusions:
- SATB2 is a critical modulator of ΔNp63α function in HNSCC.
- SATB2 expression correlates with HNSCC chemoresistance.
- Targeting SATB2 may overcome chemoresistance in HNSCC, irrespective of p53 status.
