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E3 ubiquitin ligase SMURF2 prevents colorectal cancer by reducing the stability of the YY1 protein and inhibiting the SENP1/c-myc axis

Gene Therapy volume 30, pages 51–63 (2023)Cite this article

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Abstract

Genetic association between E3 ubiquitin ligase SMURF2 and colorectal cancer (CRC) has been identified, while the mechanism remains undefined. Tumor-promoting gene YY1 represents a downstream factor of SMURF2. The study was designed to evaluate the effect of SMURF2 on the malignant phenotypes of CRC cells and the underlying mechanism. The expression pattern of SMURF2 and YY1 in CRC clinical tissues and cells was characterized by immunohistochemistry (IHC) and Western blot. Gain- and loss-of-function experiments were conducted to assess the effect of SMURF2 and YY1 on the behaviors of CRC cells. After bioinformatics analysis, the relationship between YY1 and SENP1 as well as between SENP1 and c-myc was determined by luciferase reporter and ChIP assays. Rescue experiments were performed to show their involvement during CRC progression. Finally, in vivo models of tumor growth were established for validation. SMURF2 was lowly expressed and YY1 was highly expressed in CRC tissues and cells. YY1 overexpression resulted in promotion of CRC cell proliferation, migration, and invasion, which could be reversed by SMURF2. Furthermore, SMURF2 could induce ubiquitination-mediated degradation of YY1, which bound to the SENP1 promoter and upregulated SENP1 expression, leading to enhancement of c-myc expression. The in vivo data revealed the suppressive role of SMURF2 gain-of-function in tumor growth through downregulation of YY1, SENP1, or c-myc. Altogether, our data demonstrate the antitumor activity of SMURF2 in CRC and the anti-tumor mechanism associated with degradation of YY1 and downregulation of SENP1/c-myc.

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Fig. 1: YY1 is highly expressed in CRC tissues and cells.
Fig. 2: Silencing or knockdown of YY1 impedes the proliferation, migration, and invasion of CRC cells and stimulates their apoptosis.
Fig. 3: SMURF2 is poorly expressed in CRC tissues and cells, and it promotes the ubiquitination and degradation of YY1.
Fig. 4: Overexpression of YY1 reverts the inhibitory effect of SMURF2 on the proliferation, migration, and invasion of CRC cells as well as the promoting effect of SMURF2 on cells apoptosis.
Fig. 5: YY1 binds to the promoter of SENP1 and elevates its expression, thus reducing the SUMOylation level of c-myc and increasing the expression of c-myc.
Fig. 6: SENP1 or c-myc silencing weakens the promoting effect of YY1 overexpression on the proliferation, migration, and invasion of CRC cells.
Fig. 7: SMURF2 degrades YY1 through ubiquitination and suppresses the SENP1/c-myc axis, thus inhibiting tumorigenicity of the CRC cells in vivo.
Fig. 8: The mechanism graph of the regulatory network and function of SMURF2 in CRC.

Availability of data and materials

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge and appreciate our colleagues for their valuable suggestions and technical assistance for this study.

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Authors and Affiliations

  1. Anorectal Department, Linyi People’s Hospital, Linyi, 276003, PR China

    Qianfu Gao, Shanchao Wang & Zeyan Zhang

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  1. Qianfu Gao
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Contributions

Conceived and designed research: QFG; Performed experiments: QFG, SCW; Analyzed data: ZYZ; Interpreted results of experiments: QFG, ZYZ; Prepared figures: SCW; Drafted manuscript: SCW; Edited and revised manuscript: QFG; Approved final version of manuscript: QFG, SCW, ZYZ.

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Correspondence to Zeyan Zhang.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was conducted with approval of the Ethics Committee of Linyi People’s Hospital and in line with the Declaration of Helsinki. All patients and/or legal guardians signed the informed consent documentation prior to sample collection. Animal experiments were approved by the Animal Ethics Committee of Linyi People’s Hospital. Great efforts were made to minimize the number of animals used in the experiments and their suffering.

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Gao, Q., Wang, S. & Zhang, Z. E3 ubiquitin ligase SMURF2 prevents colorectal cancer by reducing the stability of the YY1 protein and inhibiting the SENP1/c-myc axis. Gene Ther 30, 51–63 (2023). https://doi.org/10.1038/s41434-021-00289-z

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