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:

WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5–MDM2–p53 pathway

Oncogene volume 39, pages 2741–2755 (2020)Cite this article

Subjects

Abstract

The key molecules and underlying mechanisms of melanoma metastasis remain poorly understood. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomic screening, probing of patients’ samples, functional verification, and mechanistic validation, we identified the important role of the WD repeat-containing protein 74 (WDR74) in melanoma progression and metastasis. Through gain- and loss-of-function approaches, WDR74 was found to promote cell proliferation, apoptosis resistance, and aggressive behavior in vitro. Moreover, WDR74 contributed to melanoma growth and metastasis in vivo. Mechanistically, WDR74 modulates RPL5 protein levels and consequently regulates MDM2 and insulates the ubiquitination degradation of p53 by MDM2. Our study is the first to reveal the oncogenic role of WDR74 in melanoma progression and the regulatory effect of WDR74 on the RPL5–MDM2-p53 pathway. Collectively, WDR74 can serve as a candidate target for the prevention and treatment of melanoma in the clinic.

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: WDR74 is upregulated in metastatic melanoma compared with that in primary melanoma.
Fig. 2: WDR74 promotes cell proliferation and cell cycle progression in A375 cells in vitro.
Fig. 3: WDR74 is associated with apoptosis resistance in A375 cells in vitro.
Fig. 4: WDR74 impacts on metastasis-related capacities in A375 cells in vitro.
Fig. 5: WDR74 regulates the RPL5–MDM2–p53 pathway.
Fig. 6: WDR74 contributes to tumor growth and distant metastasis of melanoma in nude mice.

Similar content being viewed by others

References

  1. Kressler D, Hurt E, Bassler J. Driving ribosome assembly. Biochim Biophys Acta. 1803;2010:673–83.

    Google Scholar 

  2. Pelletier J, Thomas G, Volarevic S. Ribosome biogenesis in cancer: new players and therapeutic avenues. Nat Rev Cancer. 2018;18:51–63.

    Article  CAS  PubMed  Google Scholar 

  3. Liu Y, Deisenroth C, Zhang Y. RP-MDM2-p53 pathway: linking ribosomal biogenesis and tumor surveillance. Trends Cancer. 2016;2:191–204.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Liu S, Tackmann NR, Yang J, Zhang Y. Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis. Oncogene. 2017;36:1374–83.

    Article  CAS  PubMed  Google Scholar 

  5. Lozano G. The oncogenic roles of p53 mutants in mouse models. Curr Opin Genet Dev. 2007;17:66–70.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang Y, Lu H. Signaling to p53: ribosomal proteins find their way. Cancer Cell. 2009;16:369–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang W, Nag S, Zhang X, Wang MH, Wang H, Zhou J, et al. Ribosomal proteins and human diseases: pathogenesis, molecular mechanisms, and therapeutic implications. Med Res Rev. 2015;35:225–85.

    Article  CAS  PubMed  Google Scholar 

  8. Kardos GR, Dai MS, Robertson GP. Growth inhibitory effects of large subunit ribosomal proteins in melanoma. Pigment Cell Melanoma Res. 2014;27:801–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lo YH, Romes EM, Pillon MC, Sobhany M, Stanley RE. Structural analysis reveals features of ribosome assembly factor Nsa1/WDR74 important for localization and interaction with Rix7/NVL2. Structure. 2017;25:762.e4–72.

    Article  CAS  Google Scholar 

  10. Hiraishi N, Ishida YI, Sudo H, Nagahama M. WDR74 participates in an early cleavage of the pre-rRNA processing pathway in cooperation with the nucleolar AAA-ATPase NVL2. Biochem Biophys Res Commun. 2018;495:116–23.

    Article  CAS  PubMed  Google Scholar 

  11. Maserati M, Walentuk M, Dai X, Holston O, Adams D, Mager J. Wdr74 is required for blastocyst formation in the mouse. Plos ONE. 2011;6:e22516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Krol M, Polanska J, Pawlowski KM, Turowski P, Skierski J, Majewska A, et al. Transcriptomic signature of cell lines isolated from canine mammary adenocarcinoma metastases to lungs. J Appl Genet. 2010;51:37–50.

    Article  CAS  PubMed  Google Scholar 

  13. üri Reimand. Network-driven discovery of cancer drivers and pathways using 2,500 whole cancer genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting. 1–5 April 2017, Washington, DC. Philadelphia (PA): AACR; Cancer Res. 2017;77(13 Suppl):Abstract nr 385. https://doi.org/10.1158/1538-7445.AM2017-385.

  14. Paradiso V, Garofoli A, Tosti N, Lanzafame M, Perrina V, Quagliata L, et al. Diagnostic targeted sequencing panel for hepatocellular carcinoma genomic screening. J Mol Diagn. 2018;20:836–48.

    Article  CAS  PubMed  Google Scholar 

  15. Weinhold N, Jacobsen A, Schultz N, Sander C, Lee W. Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet. 2014;46:1160–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang F, Song W, Li S, Ajay V, Aguilo F, Bagchi A, et al. Abstract PR06: the enhancer landscape involves a core noncoding RNA protein interaction network for C-MYC expression. Cancer Res. 2016;76:PR06.

    Google Scholar 

  17. Yoshikatsu Yuki, Ishida Yo-ichi, Sudo Haruka, Yamazoe T, Kawate Y, Shinohara T, et al. NVL2 Is a nucleolar AAA-ATPase that Interacts with ribosomal protein L5 through Its nucleolar localization sequence. Biochem Biophys Res Commun. 2015;464:780–6.

    Article  CAS  PubMed  Google Scholar 

  18. Owens. Melanoma. Nature. 20;515(7527):S109.

  19. Bedrosian I, Faries MB, Guerry DT, Elenitsas R, Schuchter L, Mick R, et al. Incidence of sentinel node metastasis in patients with thin primary melanoma (< or = 1 mm) with vertical growth phase. Ann Surg Oncol. 2000;7:262–7.

    Article  CAS  PubMed  Google Scholar 

  20. Damsky WE, Theodosakis N, Bosenberg M. Melanoma metastasis: new concepts and evolving paradigms. Oncogene. 2014;33:2413–22.

    Article  CAS  PubMed  Google Scholar 

  21. Liang W, Li Q, Ferrara N. Metastatic growth instructed by neutrophil-derived transferrin. Proc Natl Acad Sci USA. 2018;115:11060–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545:175–80.

    Article  CAS  PubMed  Google Scholar 

  23. Li B, Shen W, Peng H, Li Y, Chen F, Zheng L, et al. Fibronectin 1 promotes melanoma proliferation and metastasis by inhibiting apoptosis and regulating EMT. Onco Targets Ther. 2019;12:3207–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kitatani K, Usui T, Sriraman SK, Toyoshima M, Ishibashi M, Shigeta S, et al. Ceramide limits phosphatidylinositol-3-kinase C2beta-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene. 2016;35:2801–12.

    Article  CAS  PubMed  Google Scholar 

  25. Srivastava SK, Bhardwaj A, Arora S, Singh S, Azim S, Tyagi N, et al. MYB is a novel regulator of pancreatic tumour growth and metastasis. Br J Cancer. 2015;113:1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zetter BR. Adhesion molecules in tumor metastasis. Semin Cancer Biol. 1993;4:219–29.

    CAS  PubMed  Google Scholar 

  27. Miliani DMP, Zhang Y. The RP-Mdm2-p53 pathway and tumorigenesis. Oncotarget. 2011;2:234–8.

    Google Scholar 

  28. Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH. Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol. 2013;14:32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ozdemir E, Kakehi Y, Yoshida O. p21(WAF-1/CIP-1), a downstream regulator of functional p53 loss, in transitional cell carcinoma of urothelium. Eur Urol. 2000;38:230–4.

    Article  CAS  PubMed  Google Scholar 

  30. Chen X, Zeng K, Xu M, Liu X, Hu X, Xu T, et al. P53-induced miR-1249 inhibits tumor growth, metastasis, and angiogenesis by targeting VEGFA and HMGA2. Cell Death Dis. 2019;10:131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ossio R, Roldan-Marin R, Martinez-Said H, Adams DJ, Robles-Espinoza CD. Melanoma: a global perspective. Nat Rev Cancer. 2017;17:393–4.

    Article  CAS  PubMed  Google Scholar 

  32. Little EG, Eide MJ. Update on the current state of melanoma incidence. Dermatol Clin. 2012;30:355–61.

    Article  CAS  PubMed  Google Scholar 

  33. Neer EJ, Schmidt CJ, Nambudripad R, Smith TF. The ancient regulatory-protein family of WD-repeat proteins. Nature. 1994;371:297–300.

    Article  CAS  PubMed  Google Scholar 

  34. Liu J, Zhao M, Yuan B, Gu S, Zheng M, Zou J, et al. WDR74 functions as a novel coactivator in TGF-beta signaling. J Genet Genom. 2018;45:639–50.

    Article  Google Scholar 

  35. Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, et al. A global map of p53 transcription-factor binding sites in the human genome. Cell. 2006;124:207–19.

    Article  CAS  PubMed  Google Scholar 

  36. Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 2018;25:114–32.

    Article  CAS  PubMed  Google Scholar 

  37. Lin CP, Lin CS, Lin HH, Li KT, Kao SH, Tsao SM. Bergapten induces G1 arrest and pro-apoptotic cascade in colorectal cancer cells associating with p53/p21/PTEN axis. Environ Toxicol. 2019;34:303–11.

    Article  CAS  PubMed  Google Scholar 

  38. Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. Faseb J. 2001;15:1667–9.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang Q, Lu S, Li T, Yu L, Zhang Y, Zeng H, et al. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. J Exp Clin Cancer Res. 2019;38:173.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Chen X, Xu X, Pan B, Zeng K, Xu M, Liu X, et al. miR-150-5p suppresses tumor progression by targeting VEGFA in colorectal cancer. Aging. 2018;10:3421–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang S, Xiao Z, Hong Z, Jiao H, Zhu S, Zhao Y, et al. FOXF1 promotes angiogenesis and accelerates bevacizumab resistance in colorectal cancer by transcriptionally activating VEGFA. Cancer Lett. 2018;439:78–90.

    Article  CAS  PubMed  Google Scholar 

  42. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev. 2006;20:2149–82.

    Article  CAS  PubMed  Google Scholar 

  44. Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13:83–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6:909–23.

    Article  CAS  PubMed  Google Scholar 

  46. Han Y, Lee H, Park JC, Yi G. E3Net: a system for exploring E3-mediated regulatory networks of cellular functions. Mol Cell Proteom. 2012;11:O111.014076.

    Article  CAS  Google Scholar 

  47. Fahraeus R, Olivares-Illana V. MDM2’s social network. Oncogene. 2014;33:4365–76.

    Article  CAS  PubMed  Google Scholar 

  48. Azim HA, Peccatori FA, Brohée S, Branstetter D, Loi S, Viale G, et al., RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy. Breast Cancer Res. 2015;17:24.

  49. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res. 2011;10:1794–805.

    Article  CAS  PubMed  Google Scholar 

  50. Zheng N, Chen J, Li T, Liu W, Liu J, Chen H, et al. Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention. Mol Carcinog. 2017;56:1896–908.

    Article  CAS  PubMed  Google Scholar 

  51. Cheng Y, Lu Y, Zhang D, Lian S, Liang H, Ye Y, et al. Metastatic cancer cells compensate for low energy supplies in hostile microenvironments with bioenergetic adaptation and metabolic reprogramming. Int J Oncol. 2018;53:2590–604.

    CAS  PubMed  Google Scholar 

  52. Zheng N, Chen J, Liu W, Wang J, Liu J, Jia L. Metapristone (RU486 derivative) inhibits cell proliferation and migration as melanoma metastatic chemopreventive agent. Biomed Pharmacother. 2017;90:339–49.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Gang Liu and Yingying Zhang for technical help in gene construct, Rong Xiang in pathology examination assistance.

Funding

This work was supported by the grants from National Natural Science Foundation of China (81961138017, 81773063, U1505225); Ministry of Science and Technology of China (2015CB931804).

Author information

Authors and Affiliations

  1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, 350116, Fujian, China

    Yumei Li, Yu Zhou, Bifei Li, Fan Chen, Weiyu Shen & Lee Jia

  2. Institute of Oceanography, Minjiang University, Fuzhou, 350116, Fujian, China

    Yusheng Lu, Chunlian Zhong, Chen Zhang, Huanzhang Xie, Vladimir L. Katanaev & Lee Jia

  3. Natural Products Drug Discovery Laboratory, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia

    Vladimir L. Katanaev

  4. Department of Cell Physiology and Metabolism, Translational Research Center in Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Vladimir L. Katanaev

Authors
  1. Yumei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bifei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weiyu Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yusheng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chunlian Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Huanzhang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vladimir L. Katanaev
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lee Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vladimir L. Katanaev or Lee Jia.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Zhou, Y., Li, B. et al. WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5–MDM2–p53 pathway. Oncogene 39, 2741–2755 (2020). https://doi.org/10.1038/s41388-020-1179-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-1179-6

This article is cited by

Search

Advanced search

Quick links