Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways.
Melanoma is one of the most aggressive cancers, and its incidence is increasing. These tumors derive from the melanocyte lineage and remain incurable after metastasis. Here we report that SONIC HEDGEHOG (SHH)-GLI signaling is active in the matrix of human hair follicles, and that it is required for the normal proliferation of human melanocytes in culture. SHH-GLI signaling also regulates the proliferation and survival of human melanomas: the growth, recurrence, and metastasis of melanoma xenografts in mice are prevented by local or systemic interference of HH-GLI function. Moreover, we show that oncogenic RAS-induced melanomas in transgenic mice express Gli1 and require Hh-Gli signaling in vitro and in vivo. Finally, we provide evidence that endogenous RAS-MEK and AKT signaling regulate the nuclear localization and transcriptional activity of GLI1 in melanoma and other cancer cells. Our data uncover an unsuspected role of HH-GLI signaling in melanocytes and melanomas, demonstrate a role for this pathway in RAS-induced tumors, suggest a general integration of the RAS/AKT and HH-GLI pathways, and open a therapeutic approach for human melanomas.
Stecca
Barbara
B
Department of Genetic Medicine and Development, University of Geneva School of Medicine, 1 Rue Michel Servet, 1211 Geneva, Switzerland.
Mas
Christophe
C
Clement
Virginie
V
Zbinden
Marie
M
Correa
Rafael
R
Piguet
Vincent
V
Beermann
Friedrich
F
Ruiz i Altaba
Ariel
A
D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000378:metabolism; D052816:Foreskin / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D014183:Transplantation, Heterologous; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases