2. Academic Validation
  3. UBE2S interacting with TRIM21 mediates the K11-linked ubiquitination of LPP to promote the lymphatic metastasis of bladder cancer

UBE2S interacting with TRIM21 mediates the K11-linked ubiquitination of LPP to promote the lymphatic metastasis of bladder cancer

  • Cell Death Dis. 2023 Jul 8;14(7):408. doi: 10.1038/s41419-023-05938-2.
Kanghua Xiao # 1 2,  Shengmeng Peng # 1 2,  Junlin Lu # 1 2,  Ting Zhou 3,  Xuwei Hong 4,  Siting Chen 1 2,  Guangyao Liu 5,  Hong Li 6,  Jian Huang 7 8 9,  Xu Chen 10 11 12,  Tianxin Lin 13 14 15
Affiliations

Affiliations

  • 1 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, PR China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, PR China.
  • 3 Biobank of Sun Yat-sen University Cancer Center, Guangzhou, 510120, Guangdong, PR China.
  • 4 Department of Urology, Shantou Central Hospital, Shantou, 515031, PR China.
  • 5 School of Medicine, South China University of Technology, Guangzhou, 510120, Guangdong, PR China.
  • 6 BioMed Laboratory, Guangzhou Jingke Biotech Group, Guangzhou, 510120, Guangdong, PR China.
  • 7 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, PR China. huangj8@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, PR China. huangj8@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, 510120, Guangdong, PR China. huangj8@mail.sysu.edu.cn.
  • 10 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, PR China. chenx457@mail.sysu.edu.cn.
  • 11 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, PR China. chenx457@mail.sysu.edu.cn.
  • 12 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, 510120, Guangdong, PR China. chenx457@mail.sysu.edu.cn.
  • 13 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, PR China. lintx@mail.sysu.edu.cn.
  • 14 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, PR China. lintx@mail.sysu.edu.cn.
  • 15 Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, 510120, Guangdong, PR China. lintx@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 37422473 DOI: 10.1038/s41419-023-05938-2
Abstract

Lymphatic metastasis is the most common pattern of bladder Cancer (BCa) metastasis and has an extremely poor prognosis. Emerging evidence shows that ubiquitination plays crucial roles in various processes of tumors, including tumorigenesis and progression. However, the molecular mechanisms underlying the roles of ubiquitination in the lymphatic metastasis of BCa are largely unknown. In the present study, through bioinformatics analysis and validation in tissue samples, we found that the ubiquitin-conjugating E2 Enzyme UBE2S was positively correlated with the lymphatic metastasis status, high tumor stage, histological grade, and poor prognosis of BCa patients. Functional assays showed that UBE2S promoted BCa cell migration and invasion in vitro, as well as lymphatic metastasis in vivo. Mechanistically, UBE2S interacted with tripartite motif containing 21 (TRIM21) and jointly induced the ubiquitination of lipoma preferred partner (LPP) via K11-linked polyubiquitination but not K48- or K63-linked polyubiquitination. Moreover, LPP silencing rescued the anti-metastatic phenotypes and inhibited the epithelial-mesenchymal transition of BCa cells after UBE2S knockdown. Finally, targeting UBE2S with cephalomannine distinctly inhibited the progression of BCa in cell lines and human BCa-derived organoids in vitro, as well as in a lymphatic metastasis model in vivo, without significant toxicity. In conclusion, our study reveals that UBE2S, by interacting with TRIM21, degrades LPP through K11-linked ubiquitination to promote the lymphatic metastasis of BCa, suggesting that UBE2S represents a potent and promising therapeutic target for metastatic BCa.

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