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The E3 ligase HUWE1 increases the sensitivity of CRC to oxaliplatin through TOMM20 degradation

Oncogene volume 43, pages 636–649 (2024)Cite this article

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Abstract

Continuous administration of oxaliplatin, the most widely used first-line chemotherapy drug for colorectal cancer (CRC), eventually leads to drug resistance. Increasing the sensitivity of CRC cells to oxaliplatin is a key strategy to overcome this issue. Impairment of mitochondrial function is a pivotal mechanism determining the sensitivity of CRC to oxaliplatin. We discovered an inverse correlation between Translocase of Outer Mitochondrial Membrane 20 (TOMM20) and oxaliplatin sensitivity as well as an inverse relationship between TOMM20 and HECT, UBA, and WWE domain containing E3 ligase 1 (HUWE1) expression in CRC. For the first time, we demonstrated that HUWE1 ubiquitinates TOMM20 directly and also regulates TOMM20 degradation via the PARKIN-mediated pathway. Furthermore, we showed that overexpression of HUWE1 in CRC cells has a negative effect on mitochondrial function, including the generation of ATP and maintenance of mitochondrial membrane potential, leading to increased production of ROS and apoptosis. This effect was amplified when cells were treated simultaneously with oxaliplatin. Our study conclusively shows that TOMM20 is a novel target of HUWE1. Our findings indicate that HUWE1 plays a critical role in regulating oxaliplatin sensitivity by degrading TOMM20 and inducing mitochondrial damage in CRC.

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Fig. 1: TOMM20 expression level and oxaliplatin sensitivity are inversely correlated in CRC cells.
Fig. 2: Dysfunction of TOMM20 ubiquitin-proteasome degradation increases the stability of TOMM20 and induces oxaliplatin resistance in CRC cells.
Fig. 3: HUWE1 modulates oxaliplatin sensitivity through the regulation of TOMM20 in CRC cells.
Fig. 4: HUWE1 specifically ubiquitinates TOMM20 leading to proteasomal degradation.
Fig. 5: HUWE1 regulates the degradation of TOMM20 leading to mitophagy in two ways: both the ubiquitin-mediated pathway and the PARKIN-mediated pathway.
Fig. 6: Overexpression of HUWE1 or suppression of TOMM20 increases oxaliplatin-induced mitochondrial dysfunction in CRC cells.
Fig. 7: Overexpression of HUWE1 induced S phase arrest in oxaliplatin-resistant CRC cells.
Fig. 8: Overexpression of HUWE1 or suppression of TOMM20 induced apoptosis in oxaliplatin-resistant CRC cells.

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All data supporting the findings of this study can be freely accessed by any researcher for non-commercial purposes upon reasonable request.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government. (MSIT) (2022R1F1A1066987, RS-2023-00273665).

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  1. Department of Biomedicine & Health Sciences, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 065-691, Republic of Korea

    Chanhaeng Lee & Sungjoo Kim Yoon

  2. Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 065-691, Republic of Korea

    Chanhaeng Lee, Sang-Hee Park & Sungjoo Kim Yoon

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CL and SKY conceived the study and designed the experiment. CL and SHP performed the experiment and analyzed the data. CL and SKY interpreted and discussed the data. CL wrote the manuscript. SKY revised the manuscript and supervised the study.

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Correspondence to Sungjoo Kim Yoon.

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Lee, C., Park, SH. & Yoon, S.K. The E3 ligase HUWE1 increases the sensitivity of CRC to oxaliplatin through TOMM20 degradation. Oncogene 43, 636–649 (2024). https://doi.org/10.1038/s41388-023-02928-8

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