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USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A

Cell Death & Differentiation volume 30, pages 2393–2407 (2023)Cite this article

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Abstract

In the current study, we have shown that USP51 promotes colorectal cancer stemness and chemoresistance, and high expression of USP51 predicts survival disadvantage in colorectal cancer patients. Mechanically, USP51 directly binds to Elongin C (ELOC) and forms a larger functional complex with VHL E3 ligase (USP51/VHL/CUL2/ELOB/ELOC/RBX1) to regulate the ubiquitin-dependent proteasomal degradation of HIF1A. USP51 efficiently deubiquitinates HIF1A and activates hypoxia-induced gene transcription. Conversely, the activation of HIF1A under hypoxia transcriptionally upregulates the expression of USP51. Thus, USP51 and HIF1A form a positive feedback loop. Further, we found that the SUMOylation of ELOC at K32 inhibits its binding to USP51. SUMO-specific protease 1 (SENP1) mediates the deSUMOylation of ELOC, promoting the binding of USP51 to ELOC and facilitating the deubiquitination and stabilization of HIF1A by USP51. Importantly, USP51 plays a crucial role in promoting the HIF1A and SENP1-dependent proliferation, migration, stemness, and chemoresistance under hypoxia in colorectal cancer. Together, our data revealed that USP51 is an oncogene stabilizing the pro-survival protein HIF1A, offering a potential therapeutic target for colorectal cancer.

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Fig. 1: USP51 can effectively prevent HIF1A protein degradation by deubiquitination.
Fig. 2: USP51 interacts with HIF1A via direct binding to ELOC.
Fig. 3: SENP1-mediated ELOC deSUMOylation promotes USP51 binding to ELOC.
Fig. 4: USP51 is a direct target gene of HIF1A.
Fig. 5: Both HIF1A and SENP1 are required for USP51 to promote CRC proliferation, migration, and stemness under hypoxia.
Fig. 6: Both HIF1A and SENP1 are required for USP51 to promote CRC chemoresistance under hypoxia.
Fig. 7: High expression of USP51 predicts survival disadvantage in colorectal cancer.

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All data needed to evaluate the conclusions in the paper are present in the paper. Additional data related to this paper may be requested from the corresponding author.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 82002547).

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Authors and Affiliations

  1. Department of General Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China

    Mingchao Mu, Chenye Zhao, Xiaopeng Li, Zilu Chen, Xuejun Sun & Junhui Yu

  2. Department of Dermatology, Northwest Hospital, the Second Affiliated Hospital of Xi’an Jiaotong University, 710004, Xi’an, Shaanxi, China

    Qin Zhang

  3. Department of Radiation Oncology, the First Affiliated Hospital of Xi’an Jiaotong University, 710061, Xi’an, Shaanxi, China

    Jing Li

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Contributions

MM and QZ: Conceptualization, methodology, validation, original draft writing, review & editing. JL: Conducted animal experiments. YZ, XL, and ZC: Analyzed the data. XS: Conceptualization, supervision, project administration. JY: Supervision, project administration, investigation, methodology, resourcing, review & editing of the manuscript.

Corresponding authors

Correspondence to Xuejun Sun or Junhui Yu.

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The authors declare no competing interests.

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All related experiments in our study were carried out in accordance with the Helsinki Declaration, and approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University.

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Mu, M., Zhang, Q., Li, J. et al. USP51 facilitates colorectal cancer stemness and chemoresistance by forming a positive feed-forward loop with HIF1A. Cell Death Differ 30, 2393–2407 (2023). https://doi.org/10.1038/s41418-023-01228-8

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