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SUMOylation of RNF146 results in Axin degradation and activation of Wnt/β-catenin signaling to promote the progression of hepatocellular carcinoma

Oncogene volume 42, pages 1728–1740 (2023)Cite this article

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Abstract

Aberrant SUMOylation contributes to the progression of hepatocellular carcinoma (HCC), yet the molecular mechanisms have not been well elucidated. RING-type E3 ubiquitin ligase RNF146 is a key regulator of the Wnt/β-catenin signaling pathway, which is frequently hyperactivated in HCC. Here, it is identified that RNF146 can be modified by SUMO3. By mutating all lysines in RNF146, we found that K19, K61, K174 and K175 are the major sites for SUMOylation. UBC9/PIAS3/MMS21 and SENP1/2/6 mediated the conjugation and deconjugation of SUMO3, respectively. Furthermore, SUMOylation of RNF146 promoted its nuclear localization, while deSUMOylation induced its cytoplasmic localization. Importantly, SUMOylation promotes the association of RNF146 with Axin to accelerate the ubiquitination and degradation of Axin. Intriguingly, only UBC9/PIAS3 and SENP1 can act at K19/K175 in RNF146 and affect its role in regulating the stability of Axin. In addition, inhibiting RNF146 SUMOylation suppressed the progression of HCC both in vitro and in vivo. And, patients with higher expression of RNF146 and UBC9 have the worst prognosis. Taken together, we conclude that RNF146 SUMOylation at K19/K175 promotes its association with Axin and accelerates Axin degradation, thereby enhancing β-catenin signaling and contributing to cancer progression. Our findings reveal that RNF146 SUMOylation is a potential therapeutic target in HCC.

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Fig. 1: RNF146 is SUMOylated by SUMO3 at lysine 19, lysine 61, and lysine 174/175.
Fig. 2: PIAS3 and MMS21 are the dominant SUMO E3 ligases for RNF146.
Fig. 3: SENP1/2/6 are the dominant deSUMOylases responsible for removing SUMOylation from RNF146.
Fig. 4: SUMOylation at lysine 19 and lysine 175 promotes the degradation of Axin and upregulation of β-catenin.
Fig. 5: RNF146 SUMOylation activates β-catenin signaling and promotes the proliferation of HCC cells in vitro.
Fig. 6: Abolishing RNF146 SUMOylation inhibits HCC cell tumorigenesis.
Fig. 7: The clinical significance of RNF146 SUMOylation/Axin/β-catenin axis in human HCC tissues.
Fig. 8: Schematic model of the SUMO-RNF146-Axin pathway.

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Data availability

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

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Acknowledgements

This study was funded by grants from the National Key Research and Development Program of China (2021YFA0909300), the Natural Science Foundation of China (82073067, 81872140, 81621004, 81420108026 and 82172636); Guangdong Science and Technology Department (2019B020226003, 2021A0505030084, 2020B1212060018, and 2020B1212030004); Tip-top Scientific and Technical Innovative Youth Talents of Guangdong special support program (2021TQ06Y125); The Key R & D and promotion in Henan Province (212102310114).

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Author notes

  1. These authors contributed equally: Wenjia Li, Qingfang Han, Yuanxin Zhu, Yingshi Zhou.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Wenjia Li, Yuanxin Zhu, Yingshi Zhou, Jingyuan Zhang, Yuntan Qiu, Kaishun Hu & Dong Yin

  2. Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China

    Wenjia Li

  3. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Qingfang Han & Long Liu

  4. Henan Research Centre for Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Qingfang Han & Long Liu

  5. Department of Orthopedics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China

    Yuanxin Zhu

  6. Department of Ultrasound Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Yingshi Zhou

  7. Department of Oncology Radiotherapy, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421000, China

    Weijun Wu

  8. Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China

    Yu Li

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Contributions

Research conception and design: DY, KSH, WJL, QFH; Experimental of methodology: KSH, WJL, YXZ, YL, WJW; Acquisition of data (provided animals, patient samples and provided facilities, etc.): QFH, JYZ, YSZ; Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): KSH, WJL, QFH, YXZ, YL, YSZ, YTQ; Write manuscript: KSH, WJL, QFH; Technical, or material support (e.g., organizing data, constructing databases,): QFH, LL, KSH.

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Correspondence to Kaishun Hu or Dong Yin.

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For the clinical specimens, ethical approval was obtained from the Ethics Committee of Sun Yat-Sen Memorial Hospital (Guangzhou, China). Informed consent was obtained from each patient. Animal study was approved by the Animal Research Committee of Sun Yat-sen University Cancer Center. Ethical approval was obtained from the Ethics Committee of Sun Yat-Sen Memorial Hospital (Guangzhou, China).

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Li, W., Han, Q., Zhu, Y. et al. SUMOylation of RNF146 results in Axin degradation and activation of Wnt/β-catenin signaling to promote the progression of hepatocellular carcinoma. Oncogene 42, 1728–1740 (2023). https://doi.org/10.1038/s41388-023-02689-4

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