Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, People's Republic of China.
Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200001, People's Republic of China.
BMC Med. 2022 Jul 1;20(1):231. doi: 10.1186/s12916-022-02409-x.
Cisplatin resistance is one of the main causes of treatment failure and death in head and neck squamous cell carcinoma (HNSCC). A more comprehensive understanding of the cisplatin resistance mechanism and the development of effective treatment strategies are urgent.
RNA sequencing, RT-PCR, and immunoblotting were used to identify differentially expressed genes associated with cisplatin resistance. Gain- and loss-of-function experiments were performed to detect the effect of CREB5 on cisplatin resistance and mitochondrial apoptosis in HNSCC. Chromatin immunoprecipitation (ChIP) assay, dual-luciferase reporter assay, and immunoblotting experiments were performed to explore the underlying mechanisms of CREB5.
CREB5 was significantly upregulated in cisplatin-resistant HNSCC (CR-HNSCC) patients, which was correlated with poor prognosis. CREB5 overexpression strikingly facilitated the cisplatin resistance of HNSCC cells in vitro and in vivo, while CREB5 knockdown enhanced cisplatin sensitivity in CR-HNSCC cells. Interestingly, the activation of AKT signaling induced by cisplatin promoted nucleus translocation of CREB5 in CR-HNSCC cells. Furthermore, CREB5 transcriptionally activated TOP1MT expression depending on the canonical motif. Moreover, CREB5 silencing could trigger mitochondrial apoptosis and overcome cisplatin resistance in CR-HNSCC cells, which could be reversed by TOP1MT overexpression. Additionally, double-targeting of CREB5 and TOP1MT could combat cisplatin resistance of HNSCC in vivo.
Our findings reveal a novel CREB5/TOP1MT axis conferring cisplatin resistance in HNSCC, which provides a new basis to develop effective strategies for overcoming cisplatin resistance.
顺铂耐药性是头颈部鳞状细胞癌（HNSCC）治疗失败和死亡的主要原因之一。更全面地了解顺铂耐药机制并开发有效的治疗策略迫在眉睫。
使用 RNA 测序、RT-PCR 和免疫印迹法鉴定与顺铂耐药相关的差异表达基因。进行增益和缺失功能实验，以检测 CREB5 对 HNSCC 顺铂耐药和线粒体凋亡的影响。进行染色质免疫沉淀（ChIP）测定、双荧光素酶报告基因测定和免疫印迹实验，以探索 CREB5 的潜在机制。
CREB5 在顺铂耐药的 HNSCC（CR-HNSCC）患者中显著上调，与不良预后相关。CREB5 过表达在体外和体内显著促进了 HNSCC 细胞的顺铂耐药性，而 CREB5 敲低增强了 CR-HNSCC 细胞对顺铂的敏感性。有趣的是，顺铂诱导的 AKT 信号激活促进了 CR-HNSCC 细胞中 CREB5 的核易位。此外，CREB5 依赖于经典基序转录激活 TOP1MT 的表达。此外，CREB5 沉默可以在 CR-HNSCC 细胞中触发线粒体凋亡并克服顺铂耐药性，而过表达 TOP1MT 可以逆转这种情况。此外，在体内，双重靶向 CREB5 和 TOP1MT 可以对抗 HNSCC 的顺铂耐药性。
我们的研究结果揭示了一种新的 CREB5/TOP1MT 轴赋予 HNSCC 顺铂耐药性，为开发克服顺铂耐药性的有效策略提供了新的依据。
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