title: Regulatory and functional connection of microphthalmia-associated transcription factor and anti-metastatic pigment epithelium derived factor in melanoma.
abstract: Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
authors.forename: Asunción
authors.initials: A
authors.lastname: Fernández-Barral
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1UL, United Kingdom.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Orgaz
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Pablo
authors.initials: P
authors.lastname: Baquero
authors.affiliation: Division of Cardiovascular Medicine, Department of Medical and Health sciences, Linköping University, Linköping, Sweden.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ali
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Centre for Gene Regulation & Expression, College of Life Sciences, Universtity of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Alberto
authors.initials: A
authors.lastname: Moreno
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Tiana
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Tumor Suppressor Signaling Networks Laboratory, UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
authors.forename: Valentí
authors.initials: V
authors.lastname: Gómez
authors.affiliation: Department of Pathology, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid, Spain; Instituto de Investigación I+12, Madrid, Spain.
authors.forename: Erica
authors.initials: E
authors.lastname: Riveiro-Falkenbach
authors.affiliation: Department of Pathology, Capio-Fundación Jimenez Díaz, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cañadas
authors.affiliation: Department of Pathology, Capio-Fundación Jimenez Díaz, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zazo
authors.affiliation: INSERM U895 Team 1 and Department of Dermatology, CHU Nice, France.
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
authors.affiliation: Institute de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.affiliation: Department of Pathology, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid, Spain; Instituto de Investigación I+12, Madrid, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Rodríguez-Peralto
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Palmero
authors.affiliation: Department of Pathology, Capio-Fundación Jimenez Díaz, Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.affiliation: Division of Cardiovascular Medicine, Department of Medical and Health sciences, Linköping University, Linköping, Sweden.
authors.forename: Lasse Dahl
authors.initials: LD
authors.lastname: Jensen
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: del Peso
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain; Instituto de Investigación I+12, Madrid, Spain. Electronic address: bjimenez@iib.uam.es.
authors.forename: Benilde
authors.initials: B
authors.lastname: Jiménez
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D018450:Disease Progression; D004843:Epistasis, Genetic; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D051739:Microphthalmia-Associated Transcription Factor; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: Abbreviations; BRAF; CM; MITF; NRAS; OIS; PEDF; RGP; VGP; VM; cutaneous metastasis of melanoma; heterogeneous nuclear RNA; hnRNA; microphthalmia-associated transcription factor; neuroblastoma RAS viral (v-ras) oncogene homolog; oncogene induced senescence; pigment epithelium-derived factor; radial growth phase of melanoma; v-raf murine sarcoma viral oncogene homolog B; vertical growth phase of melanoma; visceral metastasis of melanoma