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Int J Biol Sci 2024; 20(4):1492-1508. doi:10.7150/ijbs.90774 This issue Cite

Research Paper

USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma

Xiao Xu1#, Yananlan Chen1#, Shenye Shao1#, Jifei Wang1, Jijun Shan1, Yuming Wang1, Yirui Wang1, Jiang Chang1, Tao Zhou1, Ruixiang Chen1, Shuochen Liu1, Chang Li1, Changxian Li1,2✉, Xiangcheng Li1,2,3✉

1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
2. Key Laboratory for Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
3. The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing, Jiangsu Province, China.
# These authors contributed equally to this work.

✉ Corresponding authors: Xiangcheng Li, M.D., Ph.D., Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China; Tel. (Fax): 86-25-6830-3226; drxcliedu.cn. Changxian Li, M.D., Ph.D., Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China; Tel (Fax): 86-25-6830-3225; drlicxedu.cn. More

Citation:
Xu X, Chen Y, Shao S, Wang J, Shan J, Wang Y, Wang Y, Chang J, Zhou T, Chen R, Liu S, Li C, Li C, Li X. USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma. Int J Biol Sci 2024; 20(4):1492-1508. doi:10.7150/ijbs.90774. https://www.ijbs.com/v20p1492.htm
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Abstract

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Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in cholangiocarcinoma (CCA) has not been explored. Herein, based on The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases, we found that ubiquitin-specific protease 21 (USP21) was upregulated in CCA, high USP21 level was associated with poor prognosis. In vivo and in vitro, we identified USP21 as a master regulator of CCA growth and maintenance, which directly interacted with deubiquitinates and stabilized the heat shock protein 90 (HSP90) through K48-linked deubiquitination, and in turn, this stabilization increased HIF1A expression, thus upregulating key glycolytic enzyme genes ENO2, ENO3, ALDOC, ACSS2, and then promoted aerobic glycolysis, which provided energy for CCA cell proliferation. In addition, USP21 could directly stabilize alpha-Enolase 1 (ENO1) to promote aerobic glycolysis. Furthermore, increased USP21 level enhanced chemotherapy resistance to the gemcitabine-based regimen. Taken together, we identify a USP21-regulated aerobic glycolysis mechanism that involves the USP21/HSP90/HIF1A axis and USP21/ENO1 axis in CCA tumorigenesis, which could serve as a potential target for the treatment of CCA.

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APA
Xu, X., Chen, Y., Shao, S., Wang, J., Shan, J., Wang, Y., Wang, Y., Chang, J., Zhou, T., Chen, R., Liu, S., Li, C., Li, C., Li, X. (2024). USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma. International Journal of Biological Sciences, 20(4), 1492-1508. https://doi.org/10.7150/ijbs.90774.

ACS
Xu, X.; Chen, Y.; Shao, S.; Wang, J.; Shan, J.; Wang, Y.; Wang, Y.; Chang, J.; Zhou, T.; Chen, R.; Liu, S.; Li, C.; Li, C.; Li, X. USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma. Int. J. Biol. Sci. 2024, 20 (4), 1492-1508. DOI: 10.7150/ijbs.90774.

NLM
Xu X, Chen Y, Shao S, Wang J, Shan J, Wang Y, Wang Y, Chang J, Zhou T, Chen R, Liu S, Li C, Li C, Li X. USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma. Int J Biol Sci 2024; 20(4):1492-1508. doi:10.7150/ijbs.90774. https://www.ijbs.com/v20p1492.htm

CSE
Xu X, Chen Y, Shao S, Wang J, Shan J, Wang Y, Wang Y, Chang J, Zhou T, Chen R, Liu S, Li C, Li C, Li X. 2024. USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma. Int J Biol Sci. 20(4):1492-1508.

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