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Ubiquitination-mediated degradation of SIRT1 by SMURF2 suppresses CRC cell proliferation and tumorigenesis

Oncogene volume 39, pages 4450–4464 (2020)Cite this article

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Abstract

The NAD-dependent deacetylase sirtuin 1 (SIRT1), a member of the mammalian sirtuin family, plays a pivotal role in deacetylating histone and nonhistone proteins. Recently, it has been reported that SIRT1 is upregulated in various kinds of tumors and is associated with cell growth and metastasis. However, the factors and molecular mechanism regulating its cellular levels remain to be clarified. Here, we reported that the E3 ubiquitin ligase SMURF2 interacts with SIRT1 and mediates its ubiquitination and degradation. Depletion of SMURF2 leads to SIRT1 upregulation and induces the tumor formation and growth of colorectal cancer in vitro and in vivo. Furthermore, we show a negative correlation between SIRT1 and SMURF2 expression in human colorectal cancer. Thus, we propose a novel mechanism of colorectal tumorigenesis via SIRT1 regulation by SMURF2, which could potentially give rise to a new strategy for the treatment of colorectal cancer.

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Fig. 1: SIRT1 expression was upregulated by SMURF2 deficiency.
Fig. 2: SIRT1 interacts with SMURF2.
Fig. 3: SMURF2 positively regulates SIRT1 ubiquitination.
Fig. 4: SMURF2 positively regulates SIRT1 degradation.
Fig. 5: Global identification of cancer-associated genes upon Sirt1 depletion.
Fig. 6: Depletion of SMURF2 promotes cell proliferation and tumorigenesis in CRC partially through SIRT1.
Fig. 7: Depletion of SMURF2 promotes cell migration and metastasis partially through SIRT1.
Fig. 8: SMURF2 and SIRT1 expression are reversely correlated in CRC.

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Acknowledgements

The National Natural Science Foundation of China (Grant Nos. 31571454 and 31801181), the 61st Batch of China Postdoctoral Science Fund (Grant No. 2017M610588), the Special Fund for Postdoctoral Research Projects of Chongqing City (Grant No. Xm2017080), the Fundamental Research Funds for the Central Universities (Project No. 106112017CDJQJ298833), and the funding from Key Laboratory for Experimental Teratology of the Ministry of Education of Shandong University supported this study. We also thank the Analytical and Testing Center of Chongqing University for confocal fluorescence microscopy assistance.

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Authors and Affiliations

  1. School of Life Sciences, Chongqing University, 401331, Chongqing, China

    Le Yu, Ling Dong, Hui Li, Zhong Luo & Zhenghong Lin

  2. Department of Cell Biology, Shandong University School of Medicine, 250012, Jinan, China

    Zhaojian Liu

  3. Department of Pulmonology, Southwest Hospital, Third Military Medical University, 400038, Chongqing, China

    Guangjie Duan & Xiaotian Dai

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Yu, L., Dong, L., Li, H. et al. Ubiquitination-mediated degradation of SIRT1 by SMURF2 suppresses CRC cell proliferation and tumorigenesis. Oncogene 39, 4450–4464 (2020). https://doi.org/10.1038/s41388-020-1298-0

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