Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

TRAIP suppresses bladder cancer progression by catalyzing K48-linked polyubiquitination of MYC

Oncogene volume 43, pages 470–483 (2024)Cite this article

Subjects

Abstract

TRAF-interacting protein (TRAIP), an E3 ligase containing a RING domain, has emerged as a significant contributor to maintaining genome integrity and is closely associated with cancer. Our study reveals that TRAIP shows reduced expression in bladder cancer (BLCA), which correlates with an unfavorable prognosis. In vitro and in vivo, TRAIP inhibits proliferation and migration of BLCA cells. MYC has been identified as a novel target for TRAIP, wherein direct interaction promotes K48-linked polyubiquitination at neighboring K428 and K430 residues, ultimately resulting in proteasome-dependent degradation and downregulation of MYC transcriptional activity. This mechanism effectively impedes the progression of BLCA. Restoring MYC expression reverses suppressed proliferation and migration of BLCA cells induced by TRAIP. Moreover, our results suggest that MYC may bind to the transcriptional start region of TRAIP, thereby exerting regulatory control over TRAIP transcription. Consequently, this interaction establishes a negative feedback loop that regulates MYC expression, preventing excessive levels. Taken together, this study reveals a mechanism that TRAIP inhibits proliferation and migration of BLCA by promoting ubiquitin-mediated degradation of MYC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: TRAIP expression is reduced in BLCA progression and correlated with poor prognosis.
Fig. 2: TRAIP inhibits the proliferation of BLCA in vitro and in vivo.
Fig. 3: TRAIP inhibits BLCA metastasis in vitro and in vivo.
Fig. 4: TRAIP regulates the stability of MYC through ubiquitination.
Fig. 5: TRAIP interacts with MYC.
Fig. 6: TRAIP ubiquitinates MYC at K428/430.
Fig. 7: MYC binds to the core promoter of the TRAIP gene and promotes its expression.
Fig. 8: Mechanism diagram of the study.

Similar content being viewed by others

Data availability

The RNA-seq data in the research have been uploaded to the GEO database with the accession code (GSE237002). TCGA-BLCA data were obtained from the UCSC Xena database (https://xena.ucsc.edu/). The GSE3167 [23] and GSE138295 [34] dataset was obtained from the GEO database (https://www.ncbi.nlm.nih.gov/geo/). Additional data are provided in the article or Supplementary Information.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder cancer. Nat Rev Dis Prim. 2017;3:17022.

    Article  PubMed  Google Scholar 

  3. van Hoogstraten LMC, Vrieling A, van der Heijden AG, Kogevinas M, Richters A, Kiemeney LA. Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice. Nat Rev Clin Oncol. 2023;20:287–304.

    Article  PubMed  Google Scholar 

  4. Lee SY, Lee SY, Choi Y. TRAF-interacting protein (TRIP): a novel component of the tumor necrosis factor receptor (TNFR)- and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation. J Exp Med. 1997;185:1275–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cuella-Martin R, Hayward SB, Fan X, Chen X, Huang J-W, Taglialatela A, et al. Functional interrogation of DNA damage response variants with base editing screens. Cell. 2021;184:1081–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Soo Lee N, Jin Chung H, Kim H-J, Yun Lee S, Ji J-H, Seo Y, et al. TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage. Nat Commun. 2016;7:10463.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Harley ME, Murina O, Leitch A, Higgs MR, Bicknell LS, Yigit G, et al. TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. Nat Genet. 2016;48:36–43.

    Article  CAS  PubMed  Google Scholar 

  8. Wu RA, Semlow DR, Kamimae-Lanning AN, Kochenova OV, Chistol G, Hodskinson MR, et al. TRAIP is a master regulator of DNA interstrand crosslink repair. Nature. 2019;567:267–72.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu RA, Pellman DS, Walter JC. The ubiquitin ligase TRAIP: double-edged sword at the replisome. Trends Cell Biol. 2021;31:75–85.

    Article  CAS  PubMed  Google Scholar 

  10. Li M, Wu W, Deng S, Shao Z, Jin X. TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation. Cell Death Dis. 2021;12:767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guo Z, Zeng Y, Chen Y, Liu M, Chen S, Yao M, et al. TRAIP promotes malignant behaviors and correlates with poor prognosis in liver cancer. Biomed Pharmacother. 2020;124:109857.

    Article  CAS  PubMed  Google Scholar 

  12. Kong LR, Ong RW, Tan TZ, Mohamed Salleh NAB, Thangavelu M, Chan JV, et al. Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation. Nat Commun. 2020;11:2086.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wei C, Zhao X, Wang L, Zhang H. TRIP suppresses cell proliferation and invasion in choroidal melanoma via promoting the proteasomal degradation of Twist1. FEBS Lett. 2020;594:3170–81.

    Article  CAS  PubMed  Google Scholar 

  14. Deng M, Wang N, Li Z, Chen R, Duan J, Peng Y, et al. FXR1 can bind with the CFIm25/CFIm68 complex and promote the progression of urothelial carcinoma of the bladder by stabilizing TRAF1 mRNA. Cell Death Dis. 2022;13:170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xu N, Yao Z, Shang G, Ye D, Wang H, Zhang H, et al. Integrated proteogenomic characterization of urothelial carcinoma of the bladder. J Hematol Oncol. 2022;15:76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lourenco C, Resetca D, Redel C, Lin P, MacDonald AS, Ciaccio R, et al. MYC protein interactors in gene transcription and cancer. Nat Rev Cancer. 2021;21:579–91.

    Article  CAS  PubMed  Google Scholar 

  17. Baluapuri A, Wolf E, Eilers M. Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol. 2020;21:255–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang C, Zhang J, Yin J, Gan Y, Xu S, Gu Y, et al. Alternative approaches to target Myc for cancer treatment. Signal Transduct Target Ther. 2021;6:117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Farrell AS, Sears RC. MYC degradation. Cold Spring Harb Perspect Med. 2014;4:a014365.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA. 2004;101:9085–90.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. von der Lehr N, Johansson S, Wu S, Bahram F, Castell A, Cetinkaya C, et al. The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol Cell. 2003;11:1189–1200.

    Article  PubMed  Google Scholar 

  22. Muto T, Guillamot M, Yeung J, Fang J, Bennett J, Nadorp B, et al. TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity. Cell Stem Cell. 2022;29:298–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dyrskjot L, Kruhoffer M, Thykjaer T, Marcussen N, Jensen JL, Moller K, et al. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 2004;64:4040–8.

    Article  CAS  PubMed  Google Scholar 

  24. Said N, Frierson HF, Sanchez-Carbayo M, Brekken RA, Theodorescu D. Loss of SPARC in bladder cancer enhances carcinogenesis and progression. J Clin Investig. 2013;123:751–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu J, Zhang Y, Zeng Q, Zeng H, Liu X, Wu P, et al. Delivery of RIPK4 small interfering RNA for bladder cancer therapy using natural halloysite nanotubes. Sci Adv. 2019;5:eaaw6499.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. TGF-beta-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12. Clin Cancer Res. 2014;20:1531–41.

    Article  CAS  PubMed  Google Scholar 

  27. Yuan X, Yu L, Li J, Xie G, Rong T, Zhang L, et al. ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton. Cancer Res. 2013;73:3625–37.

    Article  CAS  PubMed  Google Scholar 

  28. Duyao MP, Buckler AJ, Sonenshein GE. Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. Proc Natl Acad Sci USA. 1990;87:4727–31.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang H, Ma L, Li J, Yu Y, Zhang D, Wei J, et al. NF-kappaB1 inhibits c-Myc protein degradation through suppression of FBW7 expression. Oncotarget. 2014;5:493–505.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 2004;23:2116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Besse A, Campos AD, Webster WK, Darnay BG. TRAF-interacting protein (TRIP) is a RING-dependent ubiquitin ligase. Biochem Biophys Res Commun. 2007;359:660–4.

    Article  CAS  PubMed  Google Scholar 

  32. Karadkhelkar NM, Lin M, Eubanks LM, Janda KD. Demystifying the druggability of the MYC family of oncogenes. J Am Chem Soc. 2023;145:3259–69.

    Article  CAS  PubMed  Google Scholar 

  33. Madden SK, de Araujo AD, Gerhardt M, Fairlie DP, Mason JM. Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc. Mol Cancer. 2021;20:3.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Upton K, Modi A, Patel K, Kendsersky NM, Conkrite KL, Sussman RT, et al. Epigenomic profiling of neuroblastoma cell lines. Sci Data. 2020;7:116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhou Q, Geahlen RL. The protein-tyrosine kinase Syk interacts with TRAF-interacting protein TRIP in breast epithelial cells. Oncogene. 2009;28:1348–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chou TY, Hart GW, Dang CV. c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J Biol Chem. 1995;270:18961–5.

    Article  CAS  PubMed  Google Scholar 

  37. Bahram F, von der Lehr N, Cetinkaya C, Larsson LG. c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. Blood. 2000;95:2104–10.

    Article  CAS  PubMed  Google Scholar 

  38. Chen Y, Zhou C, Ji W, Mei Z, Hu B, Zhang W, et al. ELL targets c-Myc for proteasomal degradation and suppresses tumour growth. Nat Commun. 2016;7:11057.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol. 2006;16:318–30.

    Article  CAS  PubMed  Google Scholar 

  40. Robertson AG, Groeneveld CS, Jordan B, Lin X, McLaughlin KA, Das A, et al. Identification of differential tumor subtypes of T1 bladder cancer. Eur Urol. 2020;78:533–7.

    Article  CAS  PubMed  Google Scholar 

  41. Jonkman JEN, Cathcart JA, Xu F, Bartolini ME, Amon JE, Stevens KM, et al. An introduction to the wound healing assay using live-cell microscopy. Cell Adh Migr. 2014;8:440–51.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wang Y, Ju L, Wang G, Qian K, Jin W, Li M, et al. DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC. Nat Commun. 2023;14:2421.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li C, Ma X, Deng J, Li J, Liu Y, Zhu X, et al. Machine learning-based automated fungal cell counting under a complicated background with ilastik and ImageJ. Eng Life Sci. 2021;21:769–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15:6479–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The excellent technical assistance of Ms. Mengxue Yu, Ms. Yayun Fang, Ms. Danni Shan and Ms. Wan Xiang is gratefully acknowledged. Thanks to Dr. Yuruo Chen for exceptional assistance in editing the diagram. This study is supported by grants from the National Natural Science Foundation of China (82172985 and 82273065), the Fundamental Research Funds for the Central Universities (2042022dx0003), Science and Technology Department of Hubei Province Key Project (2022EJD001), and Research Fund of Zhongnan Hospital of Wuhan University (SWYBK01-02, YKYXM20210105, CXPT2023001 and PTYX2023016). The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Jingtian Yu, Mingxing Li, Lingao Ju.

Authors and Affiliations

  1. Department of Urology, Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

    Jingtian Yu, Mingxing Li, Yejinpeng Wang, Renjie Zhang, Wenzhi Du, Ruoyu Huang, Kaiyu Qian, Gang Wang & Xinghuan Wang

  2. Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China

    Lingao Ju, Kaiyu Qian, Gang Wang & Yu Xiao

  3. Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Fenfang Zhou

  4. Euler Technology, ZGC Life Sciences Park, Beijing, China

    Yi Zhang

  5. Center for Quantitative Biology, School of Life Sciences, Peking University, Beijing, China

    Yi Zhang

  6. Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China

    Wenzhi Du

  7. Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China

    Xinghuan Wang

  8. Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China

    Xinghuan Wang

Authors
  1. Jingtian Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingxing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingao Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fenfang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yejinpeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Renjie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wenzhi Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ruoyu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kaiyu Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yu Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xinghuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JY, LJ, GW, YX, and XW designed the study and wrote the manuscript. JY, ML performed most of the cellular and biochemical experiments. JY, ML, FZ, RZ, and RH performed the animal experiments. JY, ML, LJ, YW, YZ, WD, GW and KQ helped with data collection and assembly. JY, ML, LJ, GW, YX and XW performed data analysis and interpretation. All authors corrected the final manuscript.

Corresponding authors

Correspondence to Yu Xiao or Xinghuan Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

For human samples: this study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Zhongnan Hospital of Wuhan University (approval number: 2021125). For animal study: the study was approved by the Experimental Animal Welfare Ethics Committee, Zhongnan Hospital of Wuhan University (approval number: ZN2022271).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, J., Li, M., Ju, L. et al. TRAIP suppresses bladder cancer progression by catalyzing K48-linked polyubiquitination of MYC. Oncogene 43, 470–483 (2024). https://doi.org/10.1038/s41388-023-02922-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02922-0

Search

Advanced search

Quick links