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:

Protooncogene MYC drives human melanocyte melanogenesis and senescence

Cancer Gene Therapy volume 29, pages 1160–1167 (2022)Cite this article

Subjects

Abstract

In spite of extensive research and advances on the molecular biology of melanoma, the process of melanocytic differentiation or its relationship with proliferation is poorly understood. The role of proto-oncogenes in normal melanocyte biology is also intriguing. Proto-oncogene MYC is overexpressed in 40% of melanomas. It has been suggested that MYC can mediate senescence bypass in malignant melanocytes, an important event in melanoma development, likely in cooperation with other oncogenic pathways. However, despite the apparent importance of MYC in melanoma, its functions in normal melanocytes are unknown. We have overexpressed MYC in freshly isolated human primary melanocytes and studied the effects on melanocytic proliferation and differentiation. MYC promoted a transient activation of melanocytes including cell cycle entry, DNA damage and cell migration. Subsequently, MYC induced melanogenesis, increased cellular size and complexity and senescence. Interestingly, we also found strong expression of MYC in regions of human nevi displaying high pigmentation and high expression of senescence marker p16. The results altogether show that MYC drives melanocytic differentiation and suggest that senescence is associated with differentiation. We discuss the implications into the mechanisms governing melanocytic differentiation and the development of melanoma.

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: MYC overexpression induces melanocyte activation.
Fig. 2: MYC causes accumulation of DNA damage.
Fig. 3: MYC induces melanocytic differentiation.
Fig. 4: MYC induces melanocyte senescence.
Fig. 5: Intralesional regions within human melanocytic nevi expressing high levels of MYC display high levels of p16 and pigmentation and vice versa.
Fig. 6: Model for the action of MYC in transformed or normal melanocytes.

Similar content being viewed by others

References

  1. Leonardi GC, Falzone L, Salemi R, Zanghì A, Spandidos DA, Mccubrey JA, et al. Cutaneous melanoma: from pathogenesis to therapy (Review). Int J Oncol. 2018;52:1071–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Moehrle M. Outdoor sports and skin cancer. Clin Dermatol. 2008;26:12–5.

    Article  PubMed  Google Scholar 

  3. Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127:179–82.

    Article  CAS  PubMed  Google Scholar 

  4. Bansal R, Nikiforov MA. Pathways of oncogene-induced senescence in human melanocytic cells. Cell Cycle. 2010;9:2782–278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer MYC function. Cancer Discov. 2015;5:1024–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science. 1992;257:212–4.

    Article  CAS  PubMed  Google Scholar 

  7. Leikam C, Hufnagel A, Walz S, Kneitz S, Fekete A, Müller MJ, et al. Cystathionase mediates senescence evasion in melanocytes and melanoma cells. Oncogene. 2014;33:771–82.

    Article  CAS  PubMed  Google Scholar 

  8. Zhuang D, Mannava S, Grachtchouk V, Tang WH, Patil S, Wawrzyniak JA, et al. C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. Oncogene. 2008;27:6623–34.

    Article  CAS  PubMed  Google Scholar 

  9. Leon J, Ferrandiz N, Acosta JC, Delgado MD. Inhibition of cell differentiation: a critical mechanism for MYC-mediated carcinogenesis? Cell Cycle. 2009;8:1148–57.

    Article  CAS  PubMed  Google Scholar 

  10. Askew DS, Ashmun RA, Simmons BC, Cleveland JL. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene. 1991;6:1915–22.

    CAS  PubMed  Google Scholar 

  11. Gandarillas A. The mysterious human epidermal cell cycle, or an oncogene-induced differentiation checkpoint. Cell Cycle. 2012;11:4507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Honeycutt KA, Roop DR. c-Myc and epidermal stem cell fate determination. J Dermatol. 2004;31:368–75.

    Article  CAS  PubMed  Google Scholar 

  13. Watt FM, Frye M, Benitah SA. MYC in mammalian epidermis: how can an oncogene stimulate differentiation? Nat Rev Cancer. 2008;8:234–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cottle DL, Kretzschmar K, Schweiger PJ, Quist SR, Gollnick HP, Natsuga K, et al. c-MYC-induced sebaceous gland differentiation is controlled by an androgen receptor/p53 axis. Cell Rep. 2013;3:427–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pérez-Olivares M, Trento A, Rodriguez-Acebes S, González-Acosta D, Fernández-Antorán D, Román-García S, et al. Functional interplay between c-Myc and Max in B lymphocyte differentiation. EMBO Rep. 2018;19:1–15.

    Article  CAS  Google Scholar 

  16. Zinin N, Adameyko I, Wilhelm M, Fritz N, Uhlén P, Ernfors P, et al. MYC proteins promote neuronal differentiation by controlling the mode of progenitor cell division. EMBO Rep. 2014;15:383–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gandarillas A, Watt FM. c-Myc promotes differentiation of human epidermal stem cells. Genes Dev. 1997;11:2869–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arnold I, Watt FM. c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny. Curr Biol. 2001;11:558–68.

    Article  CAS  PubMed  Google Scholar 

  19. Pshenichnaya I, Schouwey K, Armaro M, Larue L, Paul S, Eisenman RN, et al. Constitutive gray hair in mice induced by melanocyte-specific deletion of c-Myc. Pigment Cell Melanoma Res. 2013;25:312–25.

    Article  CAS  Google Scholar 

  20. Gandarillas A, Molinuevo R, Sanz-Gomez N. Mammalian endoreplication emerges to reveal a potential developmental timer. Cell Death Differ. 2018;25:471–6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol. 2015;10:425–48.

    Article  CAS  PubMed  Google Scholar 

  22. Medrano EE, Yang F, Boissy R, Farooqui J, Shah V, Matsumoto K, et al. Terminal differentiation and senescence in the human melanocyte: repression of tyrosine-phosphorylation of the extracellular signal-regulated kinase 2 selectively defines the two phenotypes. Mol Biol Cell. 1994;5:497–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Taylor KL, Lister JA, Zeng Z, Ishizaki H, Anderson C, Kelsh RN, et al. Differentiated melanocyte cell division occurs in vivo and is promoted by mutations in Mitf. Development. 2011;138:3579–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Leikam C, Hufnagel AL, Otto C, Murphy DJ, Mühling B, Kneitz S, et al. In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells. Cell Death Dis. 2015;6:1–13.

    Article  CAS  Google Scholar 

  25. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28:436–53.

    Article  CAS  PubMed  Google Scholar 

  26. Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell. 2002;9:1031–44.

    Article  CAS  PubMed  Google Scholar 

  27. Campaner S, Amati B. Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance. Cell Div. 2012;7:1–10.

    Article  CAS  Google Scholar 

  28. DeNicola GM, Tuveson DA. RAS in cellular transformation and senescence. Eur J Cancer. 2009;45:211–6.

    Article  PubMed  Google Scholar 

  29. Eller MS, Yaar M, Gilchrest BA. DNA damage and melanogenesis. Nature. 1994;372:413–4.

    Article  CAS  PubMed  Google Scholar 

  30. Gilchrest BA, Zhai S, Eller MS, Yarosh DB, Yaar M. Treatment of human melanocytes and S91 melanoma cells with the DNA repair enzyme T4 endonuclease V enhances melanogenesis after ultraviolet irradiation. J Invest Dermatol. 1993;101:666–72.

    Article  CAS  PubMed  Google Scholar 

  31. Xia M, Chen K, Yao X, Xu Y, Yao J, Yan J, et al. Mediator MED23 links pigmentation and DNA repair through the transcription factor MITF. Cell Rep. 2017;20:1794–804.

    Article  CAS  PubMed  Google Scholar 

  32. Iritani BM, Delrow J, Grandori C, Gomez I, Klacking M, Carlos LS, et al. Modulation of T-lymphocyte development, growth and cell size by the Myc antagonist and transcriptional repressor Mad1. EMBO J. 2002;21:4820–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gong ZZ, Yamagishi E, Yamazaki M, Saito K. A constitutively expressed Myc-like gene involved in anthocyanin biosynthesis from Perilla frutescens: molecular characterization, heterologous expression in transgenic plants and transactivation in yeast cells. Plant Mol Biol. 1999;41:33–44.

    Article  CAS  PubMed  Google Scholar 

  34. Bandyopadhyay D, Medrano EE. Melanin accumulation accelerates melanocyte senescence by a mechanism involving p16INK4a/CDK4/pRB and E2F1. Ann N Y Acad sci. 2000;908:71–84.

    Article  CAS  PubMed  Google Scholar 

  35. Choi SY, Bin BH, Kim W, Lee E, Lee TR, Cho EG. Exposure of human melanocytes to UVB twice and subsequent incubation leads to cellular senescence and senescence-associated pigmentation through the prolonged p53 expression. J Dermatol Sci. 2018;90:303–12.

    Article  CAS  PubMed  Google Scholar 

  36. Thomas NE, Kricker A, Waxweiler WT, Dillon PM, Busam KJ, From L, et al. Comparison of clinicopathologic features and survival of histopathologically amelanoticand pigmented melanomas a population-based study. JAMA Dermatol. 2014;150:1306–14.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Collado M, Serrano M. The power and the promise of oncogene-induced senescence markers. Nat Rev Cancer. 2006;6:472–6.

    Article  CAS  PubMed  Google Scholar 

  38. Freije A, Sanz-Gomez N, Gandarillas A. Genetic modification of human primary keratinocytes by lentiviral vectors. Methods Mol Biol. 2020;2109:113–23.

    Article  CAS  PubMed  Google Scholar 

  39. Sanz-Gómez N, Freije A, Gandarillas A. Keratinocyte differentiation by flow cytometry. Methods Mol Biol. 2020;2109:83–92.

    Article  PubMed  CAS  Google Scholar 

  40. Freije A, Ceballos L, Coisy M, Barnes L, Rosa M, De Diego E, et al. Cyclin E drives human keratinocyte growth into differentiation. Oncogene. 2012;31:5180–92.

    Article  CAS  PubMed  Google Scholar 

  41. Ritchie A, Gutierrez O, Fernandez-Luna JL. PAR bZIP-bik is a novel transcriptional pathway that mediates oxidative stress-induced apoptosis in fibroblasts. Cell Death Differ. 2009;16:838–46.

    Article  CAS  PubMed  Google Scholar 

  42. Itahana K, Campisi J, Dimri GP. Methods to detect biomarkers of cellular senescence: the senescence-associated beta-galactosidase assay. Methods Mol Biol. 2007;371:21–31.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dolores Delgado and Javier León for reagents, Ernesto de Diego for skin biopsies, Darío Alves, Laura Ceballos, Ángel Estébanez and Ana Freije for technical support. This work was funded by Instituto de Salud Carlos III (ISCIII)-FEDER, grant PI17/01307. LSJ was supported by University of Cantabria/IDIVAL (PREVAL 19/06).

Author information

Authors and Affiliations

  1. Cell Cycle, Stem Cell Fate and Cancer Laboratory, Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain

    Lucía San Juan & Alberto Gandarillas

  2. Pathology Department, Hospital Universitario Marqués de Valdecilla (HUMV), 39008, Santander, Spain

    María Luisa Cagigal & Marta Mayorga

  3. Histopathology Department, Hospital Universitario El Bierzo, 24404, Ponferrada, Spain

    Angel Fernandez-Flores

  4. INSERM, Languedoc-Roussillon, 34394, Montpellier, France

    Alberto Gandarillas

Authors
  1. Lucía San Juan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María Luisa Cagigal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angel Fernandez-Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marta Mayorga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alberto Gandarillas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LSJ contributed experimental design, data acquisition, data analyses, writing the manuscript and figure making. MLC and AF-F provided clinical biopsies, and contributed data acquisition, characterisation and counselling. MM contributed data acquisition, characterisation and counselling. AG contributed obtaining financial support, project and experimental design, data analyses, writing the manuscript and figure making.

Corresponding author

Correspondence to Alberto Gandarillas.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

San Juan, L., Cagigal, M.L., Fernandez-Flores, A. et al. Protooncogene MYC drives human melanocyte melanogenesis and senescence. Cancer Gene Ther 29, 1160–1167 (2022). https://doi.org/10.1038/s41417-021-00424-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-021-00424-3

Search

Advanced search

Quick links