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MCPIP1 Suppresses the NF-κB Signaling Pathway Through Negative Regulation of K63-Linked Ubiquitylation of TRAF6 in Colorectal Cancer

Cancer Gene Therapy volume 30, pages 96–107 (2023)Cite this article

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Abstract

The abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is an important precipitating factor for the inception and development of colorectal cancer (CRC), one of the most common tumors worldwide. As a pro-apoptotic transcription factor, monocyte chemotactic protein-induced protein 1 (MCPIP1) has been closely associated with many tumor types. In the present study, the expression of MCPIP1 was firstly discovered reduced in CRC tissues and correlated with poor patient prognosis. The decreased expression was caused by promoter hypermethylation. Overexpressed MCPIP1 was found to inhibit the proliferative and migratory abilities of CRC cells, whereas knockdown of MCPIP1 produced the opposite result. The subsequent investigation demonstrated that MCPIP1 exerted its “anti-cancer” effect by suppression of the NF-κB signaling pathway through negative regulation of K63-linked ubiquitylation of TNF receptor associated factor 6 (TRAF6). Therefore, our results indicate a prognostic marker for CRC and a theoretical basis for MCPIP1 as a treatment.

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Fig. 1: qPCR and IHC of MCPIP1 level in CRC tissues.
Fig. 2: Methylation analysis of ZC3H12A.
Fig. 3: MCPIP1 inhibited proliferation, promoted apoptosis and inhibited migration/invasion of CRC cells.
Fig. 4: MCPIP1 negatively regulated the NF-κB pathway transcription and translation.
Fig. 5: MCPIP1 suppressed the NF-κB signaling through reducing K63-ubiquitination of TRAF6 in 293T cells.
Fig. 6: The influence of TRAF6 combined with MCPIP1 on CRC cells.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work is supported by the grants from the National Natural Science Foundation of China (No. 81702312) and the Natural Science Foundation of Guangdong Province (No. 2017A030310489).

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Author notes

  1. These authors contributed equally: Wen Ye, Yachao Cui, Jian Rong.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Wen Ye & Zhousan Zheng

  2. Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China

    Yachao Cui & Yingchang Li

  3. Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China

    Yachao Cui & Yingchang Li

  4. Department of Extracorporeal Circulation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Jian Rong

  5. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

    Wenlin Huang

  6. State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc, Guangzhou, China

    Wenlin Huang

  7. Department of Food Science and Technology, Jinan University, Guangzhou, China

    Anqi Li

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Contributions

WY, WH, and YL contributed to the conceptualization and design of the experiment. WY, JR, ZZ, and AL contributed to the methodology, investigation, and data curation. YC and YL contributed to the software, validation, and visualization. WY also contributed to the supervision and funding acquisition. All authors contributed to the data analysis, paper writing, and approved submission.

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Correspondence to Wen Ye or Yingchang Li.

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Ye, W., Cui, Y., Rong, J. et al. MCPIP1 Suppresses the NF-κB Signaling Pathway Through Negative Regulation of K63-Linked Ubiquitylation of TRAF6 in Colorectal Cancer. Cancer Gene Ther 30, 96–107 (2023). https://doi.org/10.1038/s41417-022-00528-4

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