SATB2 augments ΔNp63α in head and neck squamous cell carcinoma

Delta Np63 alpha is a critical pro-survival protein overexpressed in 80% of head and neck squamous cell carcinomas (HNSCCs) where it inhibits TAp73 beta transcription of p53-family target genes, which is thought to increase HNSCC resistance to chemotherapy-induced cell death. However, the mechanisms governing Delta Np63 alpha function are largely unknown. In this study, we identify special AT-rich-binding protein 2 (SATB2) as a new Delta Np63 alpha-binding protein that is preferentially expressed in advanced-stage primary HNSCC and show that SATB2 promotes chemoresistance by enhancing Delta Np63 alpha-mediated transrepression by augmenting Delta Np63 alpha 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 gamma-irradiation-induced apoptosis, irrespective of p53 status. These findings unveil SATB2 as a pivotal modulator of Delta Np63 alpha that governs HNSCC cell survival.