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TRIB3 confers radiotherapy resistance in esophageal squamous cell carcinoma by stabilizing TAZ

Oncogene volume 39, pages 3710–3725 (2020)Cite this article

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Abstract

Radioresistance becomes the major obstacle to reduce tumor recurrence and improve prognosis in the treatment of esophageal squamous cell carcinoma (ESCC). Thus new strategies for radioresistant ESCC are urgently needed. Herein, we reported that tribbles pseudokinase 3 (TRIB3) serves as a key regulator of radioresistance in ESCC. TRIB3 is overexpressed in ESCC tissues and cell lines. High expression of TRIB3 significantly correlates with poor radiotherapy response and prognosis in ESCC patients. Upregulation of TRIB3 in ESCC cells conferred radioresistance in vitro and in vivo by interacting with TAZ thus impeding β-TrCP-mediated TAZ ubiquitination and degradation. Conversely, silencing TRIB3 sensitized ESCC cells to ionizing radiation. More importantly, TRIB3 was significantly correlated with TAZ activation in ESCC biopsies, and patients with high expression of both TRIB3 and TAZ suffered the worst radiotherapy response and survival. Our study uncovers the critical mechanism of ESCC resistance to radiotherapy, and provides a new pharmacological opportunity for developing a mechanism-based strategy to eliminate radioresistant ESCC in clinical practice.

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Fig. 1: High expression of TRIB3 is associated with chemoradiotherapy response of esophageal squamous cell carcinoma.
Fig. 2: TRIB3 promotes radioresistance of ESCC in vitro and in vivo.
Fig. 3: TRIB3 promotes stem cell-like properties in ESCC cells.
Fig. 4: TRIB3 stabilizes and activates TAZ in ESCC.
Fig. 5: TRIB3 interacts with TAZ and impedes β-TrCP-mediated TAZ ubiquitination.
Fig. 6: TAZ is required for TRIB3-mediated radioresistance in ESCC.
Fig. 7: The clinical relevance of the TRIB3/TAZ axis and radiotherapy response in ESCC.

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Acknowledgements

We thank all members of the Song’s laboratory for their advice and technical assistance.

Funding

This work was supported by Natural Science Foundation of China (Nos. 81272487, 81874220, 81530082, 81672854, 81773106, 91740118); The Science and Technology of Guangdong Province (Nos. 2016A030308002, 2017A030306019, 2018B030311060); Guangdong Esophageal Cancer Institute Science and Technology Program (M201715).

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  1. These authors contributed equally: Sha Zhou, Shiliang Liu

Authors and Affiliations

  1. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China

    Sha Zhou, Shiliang Liu, Lei Zhao, Mengzhong Liu & Mian Xi

  2. Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China

    Chuyong Lin, Yue Li, Liping Ye, Xianqiu Wu, Yunting Jian, Ying Ouyang & Libing Song

  3. Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-senUniversity, Guangzhou, 510080, China

    Yuhu Dai

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Zhou, S., Liu, S., Lin, C. et al. TRIB3 confers radiotherapy resistance in esophageal squamous cell carcinoma by stabilizing TAZ. Oncogene 39, 3710–3725 (2020). https://doi.org/10.1038/s41388-020-1245-0

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