FANCD2 functions as a critical factor downstream of MiTF to maintain the proliferation and survival of melanoma cells.
Proteins involved in genetic stability maintenance and safeguarding DNA replication act not only against cancer initiation but could also play a major role in sustaining cancer progression. Here, we report that the FANC pathway is highly expressed in metastatic melanoma harboring the oncogenic microphthalmia-associated transcription factor (MiTF). We show that MiTF downregulation in melanoma cells lowers the expression of several FANC genes and proteins. Moreover, we observe that, similarly to the consequence of MiTF downregulation, FANC pathway silencing alters proliferation, migration and senescence of human melanoma cells. We demonstrate that the FANC pathway acts downstream MiTF and establish the existence of an epistatic relationship between MiTF and the FANC pathway. Our findings point to a central role of the FANC pathway in cellular and chromosomal resistance to both DNA damage and targeted therapies in melanoma cells. Thus, the FANC pathway is a promising new therapeutic target in melanoma treatment.
CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.|Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.|Equipe Labellisée "ARC", C3M, Nice, F-06204, France.
Julie
J
Bourseguin
Equipe Labellisée "ARC", C3M, Nice, F-06204, France.|Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.|Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France.
Caroline
C
Bonet
CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.|Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.|Equipe Labellisée "ARC", C3M, Nice, F-06204, France.
Emilie
E
Renaud
Equipe Labellisée "ARC", C3M, Nice, F-06204, France.|Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.|Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France.
Charlotte
C
Pandiani
Equipe Labellisée "ARC", C3M, Nice, F-06204, France.|Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.|Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France.
Marina
M
Boncompagni
Equipe Labellisée "ARC", C3M, Nice, F-06204, France.|Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.|Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France.
Sandy
S
Giuliano
CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.|Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.|Equipe Labellisée "ARC", C3M, Nice, F-06204, France.
Patrycja
P
Pawlikowska
Service de génétique médicale, CHU de Nice - Hôpital l'Archet 2, Nice, F-06200, France.
Houda
H
Karmous-Benailly
Equipe Labellisée "ARC", C3M, Nice, F-06204, France.|Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.|Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France.
Robert
R
Ballotti
CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.|Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.|Equipe Labellisée "ARC", C3M, Nice, F-06204, France.
Filippo
F
Rosselli
Equipe Labellisée "ARC", C3M, Nice, F-06204, France.|Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.|Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France.
Corine
C
Bertolotto
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D007211:Indoles; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000077484:Vemurafenib