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USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy

Oncogene (2024)Cite this article

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Abstract

Deubiquitinating enzymes (DUBs) are promising targets for cancer therapy because of their pivotal roles in various physiological and pathological processes. Among these, ubiquitin-specific peptidase 26 (USP26) is a protease with crucial regulatory functions. Our study sheds light on the upregulation of USP26 in colorectal cancer (CRC), in which its increased expression correlates with an unfavorable prognosis. Herein, we evidenced the role of USP26 in promoting CRC tumorigenesis in a parkin RBR E3 ubiquitin-protein ligase (PRKN) protein-dependent manner. Our investigation revealed that USP26 directly interacted with PRKN protein, facilitating its deubiquitination, and subsequently reducing its activity. Additionally, we identified the K129 site on PRKN as a specific target for USP26-mediated deubiquitination. Our research highlights that a K-to-R mutation at the site on PRKN diminishes its potential for activation and ability to mediate mitophagy. In summary, our findings underscore the significance of USP26-mediated deubiquitination in restraining the activation of the PRKN-mediated mitophagy pathway, ultimately driving CRC tumorigenesis. This study not only elucidated the multifaceted role of USP26 in CRC but also introduced a promising avenue for therapeutic exploration through the development of small molecule inhibitors targeting USP26. This strategy holds promise as a novel therapeutic approach for CRC.

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Fig. 1: USP26 is overexpressed in colon carcinoma.
Fig. 2: Inhibition of USP26 moderates CRC tumorigenesis in vivo and in vitro.
Fig. 3: USP26 depletion promotes the activation of mitophagy.
Fig. 4: USP26 directly interacts with and deubiquitinates PRKN.
Fig. 5: USP26 removes K27-linked ubiquitin conjugates from PRKN at K129.
Fig. 6: USP26-triggered tumorigenesis is mediated by PRKN.
Fig. 7: Expression of PRKN is negatively correlated with USP26 in CRC.

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Data availability

All the data and materials used in this study are available from the corresponding author upon request.

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Acknowledgements

This work is supported by the National Key Research and Development Program of China (No. 2022YFA1105303 GW) and NSFC (GW, Nos. 81974432, 81922053, and 82330084; JH, No. 82273254).

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Authors and Affiliations

  1. GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China

    Qi Wu, Zhihong Wang, Siqi Chen, Xiaowei She, Shengyu Zhu, Pengcheng Li, Lang Liu, Kangdi Li, Anyi Liu, Changsheng Huang, Yaqi Chen, Fuqing Hu, Guihua Wang & Junbo Hu

  2. The HIT Center for Life Sciences, Harbin Institute of Technology, Harbin, 150001, China

    Chongchong Zhao

  3. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Guihua Wang

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Contributions

QW, GW, and JH conceived and designed the experiments; QW, ZW, and SC conducted biochemical and cellular experiments. XS, SZ, and PL performed the animal experiments. LL, KL, AL, and CH generated the gene knock-out cell lines. YC and FH provided help for bioinformatics analysis. JH and GW gave suggestions for many experiments. QW, GW, and JH organized and analyzed the data and wrote the manuscript, which was edited by all authors.

Corresponding authors

Correspondence to Guihua Wang or Junbo Hu.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Tongji Hospital (TJ-IRB20220723). The clinical specimens randomly used in this study were obtained from the Department of Gastrointestinal Surgery, Tongji Hospital. Demographic information, including age and sex, is presented in Table S2. Animal experiments were performed strictly following the Animal Study Guideline of Huazhong University of Science and Technology (TJH-202210034).

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Wu, Q., Wang, Z., Chen, S. et al. USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy. Oncogene (2024). https://doi.org/10.1038/s41388-024-03009-0

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