SATB2 augments ΔNp63α in head and neck squamous cell carcinoma
SATB2 augments ΔNp63α in head and neck squamous cell carcinoma
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DOI：
10.1038/embor.2010.125
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发表时间：
2010-10-01
期刊：
影响因子：
7.7
通讯作者：
Irwin, Meredith S.
中科院分区：
文献类型：
--
作者：
Chung, Jacky;Lau, Joanne;Irwin, Meredith S.
Delta Np63 α是一种关键的促生存蛋白，在80%的头颈部鳞状细胞癌（HNSCCs）中过表达，它抑制p53家族靶基因的TAp73 β转录，这被认为会增加HNSCC对化疗诱导的细胞死亡的耐药性。然而，控制Delta Np63 α功能的机制在很大程度上是未知的。在这项研究中，我们发现特殊的at -富结合蛋白2 （SATB2）是一种新的Delta Np63 α结合蛋白，在晚期原发性HNSCC中优先表达，并表明SATB2通过增强Delta Np63 α与p53家族应答元件的结合，增强Delta Np63 α介导的转抑制，从而促进化疗耐药。此外，SATB2表达与HNSCC化疗耐药呈正相关，RNA干扰介导的内源性SATB2敲低使HNSCC细胞对化疗和γ照射诱导的凋亡再敏感，无论p53状态如何。这些发现揭示了SATB2是控制HNSCC细胞存活的Delta Np63 α的关键调节剂。
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.