A novel CREB5/TOP1MT axis confers cisplatin resistance through inhibiting mitochondrial apoptosis in head and neck squamous cell carcinoma

Tong Tong; Xing Qin; Yingying Jiang; Haiyan Guo; Xiaoning Wang; Yan Li; Fei Xie; Hao Lu; Peisong Zhai; Hailong Ma; Jianjun Zhang

doi:10.1186/s12916-022-02409-x

A novel CREB5/TOP1MT axis confers cisplatin resistance through inhibiting mitochondrial apoptosis in head and neck squamous cell carcinoma

BMC Med. 2022 Jul 1;20(1):231. doi: 10.1186/s12916-022-02409-x.

Authors

Tong Tong^#^{1

2

3}, Xing Qin^#¹, Yingying Jiang⁴, Haiyan Guo⁵, Xiaoning Wang⁶, Yan Li⁷, Fei Xie¹, Hao Lu¹, Peisong Zhai¹, Hailong Ma⁸, Jianjun Zhang⁹

Affiliations

¹ 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.
² Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200001, People's Republic of China.
³ Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, 200002, People's Republic of China.
⁴ Department of Dentistry, Affiliated Hospital of Weifang Medical University, Weifang, 261000, People's Republic of China.
⁵ Department of Clinical Laboratory, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China.
⁶ Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China.
⁷ Shanghai Institute of Immunology Center for Microbiota & Immune Related Diseases, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People's Republic of China.
⁸ 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. mahl21@sjtu.edu.cn.
⁹ 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. zjjbio@sjtu.edu.cn.

^# Contributed equally.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: CREB5; Cisplatin resistance; HNSCC; Mitochondrial apoptosis; TOP1MT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Apoptosis / drug effects
Cell Line, Tumor
Cisplatin* / pharmacology
Cyclic AMP Response Element-Binding Protein A* / metabolism
DNA Topoisomerases, Type I* / genetics
Drug Resistance, Neoplasm
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / genetics
Humans
Mitochondria / drug effects
Mitochondria / genetics
Mitochondria / metabolism
Signal Transduction
Squamous Cell Carcinoma of Head and Neck* / drug therapy
Squamous Cell Carcinoma of Head and Neck* / genetics

Substances

Antineoplastic Agents
CREB5 protein, human
Cyclic AMP Response Element-Binding Protein A
DNA Topoisomerases, Type I
TOP1MT protein, human
Cisplatin