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Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Research article

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

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

Published in: BMC Medicine | Issue 1/2022

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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.
Appendix
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Metadata
Title
A novel CREB5/TOP1MT axis confers cisplatin resistance through inhibiting mitochondrial apoptosis in head and neck squamous cell carcinoma
Authors
Tong Tong
Xing Qin
Yingying Jiang
Haiyan Guo
Xiaoning Wang
Yan Li
Fei Xie
Hao Lu
Peisong Zhai
Hailong Ma
Jianjun Zhang
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02409-x

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