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Control of SOX2 protein stability and tumorigenic activity by E3 ligase CHIP in esophageal cancer cells

Oncogene volume 42, pages 2315–2328 (2023)Cite this article

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Abstract

SOX2 is highly expressed and controls tumor initiation and cancer stem cell function in various squamous cell carcinomas including esophageal squamous cancer. However, the molecular mechanism leading to SOX2 overexpression in cancer is incompletely understood. Here, we identified CHIP, a chaperone-associated ubiquitin E3 ligase, as a novel negative regulator of SOX2 protein stability and tumorigenic activity in esophageal squamous carcinoma cells. We showed that CHIP interacted with SOX2 primarily via chaperone HSP70, together they catalyzed SOX2 ubiquitination and degradation via proteasome. In contrast, HSP90 promoted SOX2 stability and inhibition of HSP90 activity induced SOX2 ubiquitination and degradation. Notably, unlike the case in normal esophageal tissues where CHIP was detected in both the cytoplasm and nucleus, CHIP in clinical esophageal tumor specimens was predominantly localized in the cytoplasm. Consistent with this observation, we observed increased expression of exportin-1/CRM-1 in clinical esophageal tumor specimens. We further demonstrated that CHIP catalyzed SOX2 ubiquitination and degradation primarily in the nuclear compartment. Taken together, our study has identified CHIP as a key suppressor of SOX2 protein stability and tumorigenic activity and revealed CHIP nuclear exclusion as a potential mechanism for aberrant SOX2 overexpression in esophageal cancer. Our study also suggests HSP90 inhibitors as potential therapeutic agents for SOX2-positive cancers.

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Fig. 1: CHIP negatively controls SOX2 protein level by promoting SOX2 proteasome degradation.
Fig. 2: HSP70 bridges the interaction between CHIP and SOX2 and is required for CHIP-mediated SOX2 ubiquitination and degradation.
Fig. 3: Both TPR and U-box domains are required for downregulation of SOX2 by CHIP.
Fig. 4: CHIP suppresses esophageal cancer cell proliferation and stem cell function.
Fig. 5: Inhibition of HSP90 activity induces SOX2 degradation.
Fig. 6: CHIP is predominantly localized in the cytoplasm in esophageal tumors.
Fig. 7: CHIP targets SOX2 ubiquitination and degradation in the nucleus.

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All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

We thank all the other members of the JW laboratory for their suggestions and technical assistance. This study is supported by grants from the National Natural Science Foundation of China (32130051 to JW and 82002995 to ZW) and Science and Technology Commission of Shanghai Municipality (20JC1411500). It was also supported by the ECNU Public Platform for Innovation (011) and the Instruments Sharing Platform of the School of Life Sciences, East China Normal University.

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  1. These authors contributed equally: Li Kang, Huifang Zhang, Yaling Wang.

Authors and Affiliations

  1. Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China

    Li Kang, Huifang Zhang, Yaling Wang, Yunfeng Zhang, Zhaosu Chen, Yuanyong Huang, Zitai Chen, Jiwen Li & Jiemin Wong

  2. Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China

    Manyu Chu, Jianzhong He & Liyan Xu

  3. The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China

    Mengyang Xue

  4. Department of Obstetrics and Gynecology, ECNU Joint Center of Translational Medicine, Fengxian Central Hospital affiliated to the Southern Medical University, Shanghai, China

    Mengyang Xue, Liu Pan & Rong Zhang

  5. Department of Obstetrics and Gynecology, Jinzhou Medical University, Liaoning, China

    Liu Pan

  6. Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

    Zhen Wang

  7. Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, China

    Enmin Li

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Contributions

LK, YW, and HZ were responsible for designing and conducting most of the experiments, extracting and analyzing data, and manuscript preparation. MC, JH, EL, and LX were responsible for tumor tissue microarray preparation, analysis, and data summary. PL, MX, and ZC conducted data validation. ZC and YH provided technical assistance. JL and RZ provided supervision and management. JW was responsible for supervision, funding, and manuscript preparation.

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Correspondence to Rong Zhang or Jiemin Wong.

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Kang, L., Zhang, H., Wang, Y. et al. Control of SOX2 protein stability and tumorigenic activity by E3 ligase CHIP in esophageal cancer cells. Oncogene 42, 2315–2328 (2023). https://doi.org/10.1038/s41388-023-02745-z

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