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.
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
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.
Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder cancer. Nat Rev Dis Prim. 2017;3:17022.
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.
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.
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.
Soo Lee N, ** 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.
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.
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.
Wu RA, Pellman DS, Walter JC. The ubiquitin ligase TRAIP: double-edged sword at the replisome. Trends Cell Biol. 2021;31:75–85.
Li M, Wu W, Deng S, Shao Z, ** 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.
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.
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.
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.
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.
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.
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.
Baluapuri A, Wolf E, Eilers M. Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol. 2020;21:255–67.
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.
Farrell AS, Sears RC. MYC degradation. Cold Spring Harb Perspect Med. 2014;4:a014365.
Welcker M, Orian A, ** 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.
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.
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.
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.
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.
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.
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.
Yuan X, Yu L, Li J, **e 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.
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.
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.
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.
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.
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.
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.
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.
Zhou Q, Geahlen RL. The protein-tyrosine kinase Syk interacts with TRAF-interacting protein TRIP in breast epithelial cells. Oncogene. 2009;28:1348–56.
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.
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.
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.
Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol. 2006;16:318–30.
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.
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.
Wang Y, Ju L, Wang G, Qian K, ** W, Li M, et al. DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC. Nat Commun. 2023;14:2421.
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.
Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15:6479–83.
Acknowledgements
The excellent technical assistance of Ms. Mengxue Yu, Ms. Yayun Fang, Ms. Danni Shan and Ms. Wan **ang 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
Authors and Affiliations
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
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.
About this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-023-02922-0
- Springer Nature Limited