The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase

Ding, Xinyuan; Gu, Yuting; Jin, Min; Guo, Xin; Xue, Sudong; Tan, Caihong; Huang, Jiefang; Yang, Wanlin; Xue, Mingxing; Zhou, Qianjun; Wang, Wenjuan; Zhang, Yanyun

doi:10.7150/thno.42096

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Theranostics 2020; 10(13):6048-6060. doi:10.7150/thno.42096 This issue Cite

Research Paper

The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase

Xinyuan Ding^1,2#, Yuting Gu^3#, Min Jin^3#, Xin Guo¹, Sudong Xue², Caihong Tan⁴, Jiefang Huang³, Wanlin Yang¹, Mingxing Xue³, Qianjun Zhou^5✉, Wenjuan Wang^1✉, Yanyun Zhang^1,3✉

1. Children's Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Soochow University, Suzhou 215000, China.
2. Department of Pharmacy, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215000, China.
3. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200127, China.
4. Department of Pharmacy, The Affiliated Hospital of Jiangsu University, Zhenjiang 212000, China.
5. Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
^# These authors contributed equally to this work.

Citation:

Ding X, Gu Y, Jin M, Guo X, Xue S, Tan C, Huang J, Yang W, Xue M, Zhou Q, Wang W, Zhang Y. The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase. Theranostics 2020; 10(13):6048-6060. doi:10.7150/thno.42096. https://www.thno.org/v10p6048.htm

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Abstract

Rationale: Resistance to pemetrexed (PEM)-based chemotherapy is a major cause of progression in non-small cell lung cancer (NSCLC) patients. The deubiquitinating enzyme UCHL1 was recently found to play important roles in chemoresistance and tumor progression. However, the potential roles and mechanisms of UCHL1 in PEM resistance remain unclear.

Methods: Bioinformatics analyses and immunohistochemistry were used to evaluate UCHL1 expression in NSCLC specimens. Kaplan-Meier analysis with the log-rank test was used for survival analyses. We established PEM-resistant NSCLC cell lines by exposing them to step-wise increases in PEM concentrations, and in vitro and in vivo assays were used to explore the roles and mechanisms of UCHL1 in PEM resistance using the NSCLC cells.

Results: In chemoresistant tumors from NSCLC patients, UCHL1 was highly expressed and elevated UCHL1 expression was strongly associated with poor outcomes. Furthermore, UCHL1 expression was significantly upregulated in PEM-resistant NSCLC cells, while genetic silencing or inhibiting UCHL1 suppressed resistance to PEM and other drugs in NSCLC cells. Mechanistically, UCHL1 promoted PEM resistance in NSCLC by upregulating the expression of thymidylate synthase (TS), based on reduced TS expression after UCHL1 inhibition and re-emergence of PEM resistance upon TS restoration. Furthermore, UCHL1 upregulated TS expression, which mitigated PEM-induced DNA damage and cell cycle arrest in NSCLC cells, and also conferred resistance to PEM and other drugs.

Conclusions: It appears that UCHL1 promotes PEM resistance by upregulating TS in NSCLC cells, which mitigated DNA damage and cell cycle arrest. Thus, UCHL1 may be a therapeutic target for overcoming PEM resistance in NSCLC patients.

Keywords: non-small cell lung cancer, chemoresistance, pemetrexed, UCHL1, thymidylate synthase

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APA

Ding, X., Gu, Y., Jin, M., Guo, X., Xue, S., Tan, C., Huang, J., Yang, W., Xue, M., Zhou, Q., Wang, W., Zhang, Y. (2020). The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase. Theranostics, 10(13), 6048-6060. https://doi.org/10.7150/thno.42096.

ACS

Ding, X.; Gu, Y.; Jin, M.; Guo, X.; Xue, S.; Tan, C.; Huang, J.; Yang, W.; Xue, M.; Zhou, Q.; Wang, W.; Zhang, Y. The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase. Theranostics 2020, 10 (13), 6048-6060. DOI: 10.7150/thno.42096.

NLM

CSE

Ding X, Gu Y, Jin M, Guo X, Xue S, Tan C, Huang J, Yang W, Xue M, Zhou Q, Wang W, Zhang Y. 2020. The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase. Theranostics. 10(13):6048-6060.

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