Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression (original) (raw)

Abbreviations

_β_-Cat:

_β_-Catenin

BCL-2:

B-Cell CLL/Lymphoma 2

bHLH:

basic Helix Loop Helix

BRAF:

viral RAF murine sarcoma viral oncogene homolog B1

Cdkn2a:

cyclin-dependent kinase inhibitor 2A

ChIP:

chromatin immunoprecipitation

c-MYC:

cellular myelocytomatosis oncogene cellular homolog

CRE:

cyclisation recombination

CTRL:

control

DCT:

dopachrome tautomerase

E:

embryonic day

EDN3/EDNRB:

endothelin 3/endothelin receptor B

ERK:

extracellular signal-regulated kinase

EMT:

epithelial-to-mesenchymal transition

FL:

floxed

HF:

hair follicle

KD:

knockdown

LacZ:

_β_-D-galactosidase

MC1R:

melanocortin 1 receptor

MCKO:

melanocyte-specific knockout

MCWT:

melanocyte-specific wild-type

MEK:

MAPK/ERK kinase

MITF:

microphthalmia-associated transcription factor

P:

postnatal day

PAX3:

paired-box 3

PGP:

P-glycoprotein

PMEL:

premelanosome protein

NHM:

normal human primary melanocytes

NRAS:

neuroblastoma RAS viral oncogene homolog

qRT-PCR:

quantitative reverse transcription-polymerase chain reaction

S100b:

S100 calcium-binding protein B

shRNA:

short hairpin RNA

siRNA:

short interfering RNA

SOX10:

sex-determining region Y (SRY)-box 10

TG:

transgenic

TGF-β:

transforming growth factor β

TYRP1:

tyrosinase-related protein 1

TYR:

tyrosinase

UV:

ultraviolet

X-gal:

5-bromo-4-chloro-3-indolyl-_β_-D-galactopyranoside

ZEB:

zinc finger E-box binding protein

References

  1. Ernfors P . Cellular origin and developmental mechanisms during the formation of skin melanocytes. Exp Cell Res 2010; 316: 1397–1407.
    Article CAS Google Scholar
  2. Luciani F, Champeval D, Herbette A, Denat L, Aylaj B, Martinozzi S et al. Biological and mathematical modeling of melanocyte development. Development 2011; 138: 3943–3954.
    Article CAS Google Scholar
  3. Osawa M . Melanocyte stem cells (June 30, 2009), StemBook, ed. The Stem Cell Research Community, StemBook, doi:10.3824/stembook.1.46.1.
  4. Pshenichnaya I, Schouwey K, Armaro M, Larue L, Knoepfler PS, Eisenman RN et al. Constitutive gray hair in mice induced by melanocyte-specific deletion of c-Myc. Pigment Cell Melanoma Res 2012; 25: 312–325.
    Article CAS Google Scholar
  5. Steingrimsson E, Copeland NG, Jenkins NA . Melanocyte stem cell maintenance and hair graying. Cell 2005; 121: 9–12.
    Article CAS Google Scholar
  6. White RM, Zon LI . Melanocytes in development, regeneration, and cancer. Cell Stem Cell 2008; 3: 242–252.
    Article CAS Google Scholar
  7. Kubic JD, Young KP, Plummer RS, Ludvik AE, Lang D . Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease. Pigment Cell Melanoma Res 2008; 21: 627–645.
    Article CAS Google Scholar
  8. Hearing VJ . Determination of melanin synthetic pathways. J Invest Dermatol 2011; 131: E8–E11.
    Article Google Scholar
  9. Schiaffino MV . Signaling pathways in melanosome biogenesis and pathology. Int J Biochem Cell Biol 2010; 42: 1094–1104.
    Article CAS Google Scholar
  10. Nishimura EK, Granter SR, Fisher DE . Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 2005; 307: 720–724.
    Article CAS Google Scholar
  11. Moriyama M, Osawa M, Mak SS, Ohtsuka T, Yamamoto N, Han H et al. Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol 2006; 173: 333–339.
    Article CAS Google Scholar
  12. Tsao H, Chin L, Garraway LA, Fisher DE . Melanoma: from mutations to medicine. Genes Dev 2012; 26: 1131–1155.
    Article CAS Google Scholar
  13. Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 2012; 18: 1239–1249.
    Article CAS Google Scholar
  14. Ackermann J, Frutschi M, Kaloulis K, McKee T, Trumpp A, Beermann F . Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. Cancer Res 2005; 65: 4005–4011.
    Article CAS Google Scholar
  15. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819.
    Article CAS Google Scholar
  16. Nazarian RM, Prieto VG, Elder DE, Duncan LM . Melanoma biomarker expression in melanocytic tumor progression: a tissue microarray study. J Cutan Pathol 2010; 37 (Suppl 1): 41–47.
    Article Google Scholar
  17. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367: 1694–1703.
    Article CAS Google Scholar
  18. Colone M, Calcabrini A, Toccacieli L, Bozzuto G, Stringaro A, Gentile M et al. The multidrug transporter P-glycoprotein: a mediator of melanoma invasion? J Invest Dermatol 2008; 128: 957–971.
    Article CAS Google Scholar
  19. Sanchez-Tillo E, Liu Y, de Barrios O, Siles L, Fanlo L, Cuatrecasas M et al. EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci 2012; 69: 3429–3456.
    Article CAS Google Scholar
  20. Thiery JP, Acloque H, Huang RY, Nieto MA . Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871–890.
    Article CAS Google Scholar
  21. Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415–428.
    Article CAS Google Scholar
  22. Sanchez-Martin M, Perez-Losada J, Rodriguez-Garcia A, Gonzalez-Sanchez B, Korf BR, Kuster W et al. Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am J Med Genet A 2003; 122A: 125–132.
    Article Google Scholar
  23. Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia A, Sanchez ML, Orfao A, Flores T et al. Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway. Blood 2002; 100: 1274–1286.
    CAS PubMed Google Scholar
  24. Jiang R, Lan Y, Norton CR, Sundberg JP, Gridley T . The Slug gene is not essential for mesoderm or neural crest development in mice. Dev Biol 1998; 198: 277–285.
    Article CAS Google Scholar
  25. Gupta PB, Kuperwasser C, Brunet JP, Ramaswamy S, Kuo WL, Gray JW et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nat Genet 2005; 37: 1047–1054.
    Article CAS Google Scholar
  26. Sanchez-Martin M, Rodriguez-Garcia A, Perez-Losada J, Sagrera A, Read AP, Sanchez-Garcia I . SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum Mol Genet 2002; 11: 3231–3236.
    Article CAS Google Scholar
  27. Shirley SH, Greene VR, Duncan LM, Torres Cabala CA, Grimm EA, Kusewitt DF . Slug expression during melanoma progression. Am J Pathol 2012; 180: 2479–2489.
    Article CAS Google Scholar
  28. Caramel J, Papadogeorgakis E, Hill L, Browne GJ, Richard G, Wierinckx A et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 2013; 24: 466–480.
    Article CAS Google Scholar
  29. Vandewalle C, Van Roy F, Berx G . The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci 2009; 66: 773–787.
    Article CAS Google Scholar
  30. Gheldof A, Hulpiau P, van Roy F, De Craene B, Berx G . Evolutionary functional analysis and molecular regulation of the ZEB transcription factors. Cell Mol Life Sci 2012; 69: 2527–2541.
    Article CAS Google Scholar
  31. Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 2001; 7: 1267–1278.
    Article CAS Google Scholar
  32. De Craene BD, Berx G . Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 2013; 13: 97–110.
    Article CAS Google Scholar
  33. Van de Putte T, Maruhashi M, Francis A, Nelles L, Kondoh H, Huylebroeck D et al. Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome. Am J Hum Genet 2003; 72: 465–470.
    Article CAS Google Scholar
  34. Van de Putte T, Francis A, Nelles L, van Grunsven LA, Huylebroeck D . Neural crest-specific removal of Zfhx1b in mouse leads to a wide range of neurocristopathies reminiscent of Mowat-Wilson syndrome. Hum Mol Genet 2007; 16: 1423–1436.
    Article CAS Google Scholar
  35. Colombo S, Champeval D, Rambow F, Larue L . Transcriptomic analysis of mouse embryonic skin cells reveals previously unreported genes expressed in melanoblasts. J Invest Dermatol 2012; 132: 170–178.
    Article CAS Google Scholar
  36. Delmas V, Martinozzi S, Bourgeois Y, Holzenberger M, Larue L . Cre-mediated recombination in the skin melanocyte lineage. Genesis 2003; 36: 73–80.
    Article CAS Google Scholar
  37. Mackenzie MA, Jordan SA, Budd PS, Jackson IJ . Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo. Dev Biol 1997; 192: 99–107.
    Article CAS Google Scholar
  38. Thurber AE, Douglas G, Sturm EC, Zabierowski SE, Smit DJ, Ramakrishnan SN et al. Inverse expression states of the BRN2 and MITF transcription factors in melanoma spheres and tumour xenografts regulate the NOTCH pathway. Oncogene 2011; 30: 3036–3048.
    Article CAS Google Scholar
  39. Strub T, Giuliano S, Ye T, Bonet C, Keime C, Kobi D et al. Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. Oncogene 2011; 30: 2319–2332.
    Article CAS Google Scholar
  40. Chin L, Garraway LA, Fisher DE . Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev 2006; 20: 2149–2182.
    Article CAS Google Scholar
  41. Southall TD, Brand AH . Neural stem cell transcriptional networks highlight genes essential for nervous system development. EMBO J 2009; 28: 3799–3807.
    Article CAS Google Scholar
  42. Xu Y, Brenn T, Brown ER, Doherty V, Melton DW . Differential expression of microRNAs during melanoma progression: miR-200c, miR-205 and miR-211 are downregulated in melanoma and act as tumour suppressors. Br J Cancer 2012; 106: 553–561.
    Article CAS Google Scholar
  43. van Kempen LC, van den Hurk K, Lazar V, Michiels S, Winnepenninckx V, Stas M et al. Loss of microRNA-200a and c, and microRNA-203 expression at the invasive front of primary cutaneous melanoma is associated with increased thickness and disease progression. Virchows Arch 2012; 461: 441–448.
    Article Google Scholar
  44. Higashi Y, Maruhashi M, Nelles L, Van de Putte T, Verschueren K, Miyoshi T et al. Generation of the floxed allele of the SIP1 (Smad-interacting protein 1) gene for Cre-mediated conditional knockout in the mouse. Genesis 2002; 32: 82–84.
    Article CAS Google Scholar
  45. Nyabi O, Naessens M, Haigh K, Gembarska A, Goossens S, Maetens M et al. Efficient mouse transgenesis using Gateway-compatible ROSA26 locus targeting vectors and F1 hybrid ES cells. Nucleic Acids Res 2009; 37: e55.
    Article Google Scholar
  46. van den Berghe V, Stappers E, Vandesande B, Dimidschstein J, Kroes R, Francis A et al. Directed migration of cortical interneurons depends on the cell-autonomous action of Sip1. Neuron 2013; 77: 70–82.
    Article CAS Google Scholar
  47. Berlin I, Luciani F, Gallagher SJ, Rambow F, Conde-Perez A, Colombo S et al. General strategy to analyse coat colour phenotypes in mice. Pigment Cell Melanoma Res 2012; 25: 117–119.
    Article Google Scholar
  48. Denecker G, Hoste E, Gilbert B, Hochepied T, Ovaere P, Lippens S et al. Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 2007; 9: 666–674.
    Article CAS Google Scholar
  49. Gallagher SJ, Luciani F, Berlin I, Rambow F, Gros G, Champeval D et al. General strategy to analyse melanoma in mice. Pigment Cell Melanoma Res 2012; 24: 987–988.
    Article Google Scholar

Download references

Acknowledgements

This research was funded by grants from the FWO, the Geconcerteerde Onderzoeksacties of Ghent University, the Stichting tegen Kanker, the Association for International Cancer Research (Scotland), the EU-FP6 framework program BRECOSM LSHC-CT-2004-503224, the EU-FP7 framework programs TuMIC 2008-201662 and Target-Melanoma (www.targetmelanoma.com). Work in the lab of ID was supported by grants from the Ligue National Contre le Cancer, the INCa, the Université de Strasbourg and the ANR. The IGBMC high throughput sequencing facility is a member of the ‘France Génomique’ consortium (ANR10-INBS-09-08). We acknowledge Riet DeRycke for expert electron microscopic analysis, Dr. Amin Bredan for critical reading of the manuscript and the members of our research group for valuable discussions. We thank Professor D Darling for providing the ZEB1 antibody, Professor K Hearing for providing the TYRP1 antibody.

Author contributions

GD, NV, ÖA, DK, JT, KL, AG, BDC, BB, ID, JCM and GB performed the experiments and analyzed the interpreted data. MVG, LB, GMU, MR, WMG, GG, DH, JvdO, LL and JH provided valuable reagents/material. GD and GB conceived-designed the project, analyzed the interpreted data and wrote the paper with inputs particularly from NV, DH, LL, JH, JCM and all other authors.

Author information

Authors and Affiliations

  1. Unit of Molecular and Cellular Oncology, Inflammation Research Center, VIB, Ghent, 9052, Belgium
    G Denecker, N Vandamme, Ö Akay, J Taminau, A Gheldof, B De Craene & G Berx
  2. Department of Biomedical Molecular Biology, Ghent University, Ghent, 9052, Belgium
    G Denecker, N Vandamme, Ö Akay, J Taminau, K Lemeire, A Gheldof, B De Craene, J Haigh & G Berx
  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France
    D Koludrovic & I Davidson
  4. Department of Dermatology, Ghent University Hospital, Ghent, 9000, Belgium
    M Van Gele & L Brochez
  5. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College, Dublin, 4, Ireland
    G M Udupi & W M Gallagher
  6. OncoMark Limited, Nova UCD, Belfield Innovation Park, University College Dublin, Belfield, Dublin, 4, Ireland
    G M Udupi, M Rafferty, B Balint & W M Gallagher
  7. Institute Jules Bordet, Brussels, Belgium
    G Ghanem
  8. Department of Development and Regeneration, Laboratory of Molecular Biology (Celgen), KU Leuven, Leuven, 3000, Belgium
    D Huylebroeck
  9. Department of Cell Biology, Erasmus MC, Rotterdam, 3015 GE, The Netherlands
    D Huylebroeck
  10. Department for Molecular Biomedical Research, Vascular Cell Biology Unit, VIB, Ghent, Belgium
    J Haigh
  11. Department of Pathology, University Hospital Leuven, KU Leuven, Leuven, Belgium
    J van den Oord
  12. Curie Institute, Developmental Genetics of Melanocytes, Centre National de la Recherche Scientifique (CNRS) UMR3347, Institut National de la Santé et de la Recherche Médicale (INSERM) U1021, Orsay, France
    L Larue
  13. Center for the Biology of Disease, Laboratory for Molecular Cancer Biology, VIB, Leuven, Belgium
    J-C Marine
  14. Center for Human Genetics, KU Leuven, Leuven, Belgium
    J-C Marine

Authors

  1. G Denecker
  2. N Vandamme
  3. Ö Akay
  4. D Koludrovic
  5. J Taminau
  6. K Lemeire
  7. A Gheldof
  8. B De Craene
  9. M Van Gele
  10. L Brochez
  11. G M Udupi
  12. M Rafferty
  13. B Balint
  14. W M Gallagher
  15. G Ghanem
  16. D Huylebroeck
  17. J Haigh
  18. J van den Oord
  19. L Larue
  20. I Davidson
  21. J-C Marine
  22. G Berx

Corresponding author

Correspondence toG Berx.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Edited by G Melino

Supplementary Information accompanies this paper on Cell Death and Differentiation website

Supplementary information

Rights and permissions

About this article

Cite this article

Denecker, G., Vandamme, N., Akay, Ö. et al. Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression.Cell Death Differ 21, 1250–1261 (2014). https://doi.org/10.1038/cdd.2014.44

Download citation