2. Academic Validation
  3. Smurf1 and Smurf2 mediated polyubiquitination and degradation of RNF220 suppresses Shh-group medulloblastoma

Smurf1 and Smurf2 mediated polyubiquitination and degradation of RNF220 suppresses Shh-group medulloblastoma

  • Cell Death Dis. 2023 Aug 3;14(8):494. doi: 10.1038/s41419-023-06025-2.
Yuwei Li # 1 2,  Huishan Wang # 1,  Bin Sun 3,  Guifeng Su 4,  Yu Cang 5,  Ling Zhao 6,  Shuhua Zhao 7,  Yan Li 8,  Bingyu Mao 9 10,  Pengcheng Ma 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
  • 2 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650203, China.
  • 3 Laboratory of Animal Tumour Models, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 Key Laboratory of Medicinal Chemistry for Natural Resource, School of Pharmacy, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China.
  • 5 Department of Urology, the Affiliated Hospital of Yunnan University, Kunming, 650021, China.
  • 6 Animal Center of Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
  • 7 The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
  • 8 Key Laboratory of Medicinal Chemistry for Natural Resource, School of Pharmacy, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China. [email protected].
  • 9 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China. [email protected].
  • 10 Center for Excellence in Animal Evolution and Genetics, Chinese of Academy of Sciences, Kunming, 650201, China. [email protected].
  • 11 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China. [email protected].
  • # Contributed equally.
PMID: 37537194 DOI: 10.1038/s41419-023-06025-2
Abstract

Sonic Hedgehog (Shh)-group medulloblastoma (MB) (Shh-MB) encompasses a clinically and molecularly distinct group of cancers originating from the developing nervous system with aberrant high Shh signaling as a causative driver. We recently reported that RNF220 is required for sustained high Shh signaling during Shh-MB progression; however, how high RNF220 expression is achieved in Shh-MB is still unclear. In this study, we found that the ubiquitin E3 Ligases Smurf1 and Smurf2 interact with RNF220, and target it for polyubiquitination and degradation. In MB cells, knockdown or overexpression of Smurf1 or Smurf2 promotes or inhibits cell proliferation, colony formation and xenograft growth, respectively, by controlling RNF220 protein levels, and thus modulating Shh signaling. Furthermore, in clinical human MB samples, the protein levels of Smurf1 or Smurf2 were negatively correlated with those of RNF220 or GAB1, a Shh-MB marker. Overall, this study highlights the importance of the Smurf1- and Smurf2-RNF220 axes during the pathogenesis of Shh-MB and provides new therapeutic targets for Shh-MB treatment.

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