Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools

Melanoma progression is associated with increased invasion and, often, decreased levels of microphthalmia-associated transcription factor (MITF). Accordingly, downregulation of MITF induces invasion in melanoma cells; however, little is known about the underlying mechanisms. Here, we report for the...

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Bibliographic Details
Published in:Oncogene 2017-01, Vol.36 (1), p.84-96
Main Authors: Bianchi-Smiraglia, A, Bagati, A, Fink, E E, Moparthy, S, Wawrzyniak, J A, Marvin, E K, Battaglia, S, Jowdy, P, Kolesnikova, M, Foley, C E, Berman, A E, Kozlova, N I, Lipchick, B C, Paul-Rosner, L M, Bshara, W, Ackroyd, J J, Shewach, D S, Nikiforov, M A
Format: Article
Language:English
Subjects:
Animals
Care and treatment
Cell division
Cell Line, Tumor
Cellular signal transduction
Development and progression
Disease Models, Animal
Disease Progression
Ectopic Gene Expression
Extracellular Matrix - metabolism
Female
Gene Expression Regulation, Neoplastic
Genetic aspects
GMP Reductase - genetics
GMP Reductase - metabolism
Guanosine Triphosphate - metabolism
Health aspects
Heterografts
Humans
Inhibitor drugs
Intracellular Space - metabolism
Melanocytes - metabolism
Melanoma
Melanoma - metabolism
Melanoma - pathology
Melanoma, Experimental
Mice
Microphthalmia-Associated Transcription Factor - metabolism
Microphthalmos
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
rho GTP-Binding Proteins - metabolism
Transcription factors
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Summary:Melanoma progression is associated with increased invasion and, often, decreased levels of microphthalmia-associated transcription factor (MITF). Accordingly, downregulation of MITF induces invasion in melanoma cells; however, little is known about the underlying mechanisms. Here, we report for the first time that depletion of MITF results in elevation of intracellular GTP levels and increased amounts of active (GTP-bound) RAC1, RHO-A and RHO-C. Concomitantly, MITF-depleted cells display larger number of invadopodia and increased invasion. We further demonstrate that the gene for guanosine monophosphate reductase (GMPR) is a direct MITF target, and that the partial repression of GMPR accounts mostly for the above phenotypes in MITF-depleted cells. Reciprocally, transactivation of GMPR is required for MITF-dependent suppression of melanoma cell invasion, tumorigenicity and lung colonization. Moreover, loss of GMPR accompanies downregulation of MITF in vemurafenib-resistant BRAF -melanoma cells and underlies the increased invasion in these cells. Our data uncover novel mechanisms linking MITF-dependent inhibition of invasion to suppression of guanylate metabolism.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2016.178