HACE1 is an E3 ubiquitin ligase described as a tumour suppressor because HACE1-knockout mice develop multi-organ, late-onset cancers and because HACE1 expression is lost in several neoplasms, such as Wilms’ tumours and colorectal cancer. However, a search of public databases indicated that HACE1 expression is maintained in melanomas. We demonstrated that HACE1 promoted melanoma cell migration and adhesion in vitro and was required for mouse lung colonisation by melanoma cells in vivo. Transcriptomic analysis of HACE1-depleted melanoma cells revealed an inhibition of ITGAV and ITGB1 as well changes in other genes involved in cell migration. We revealed that HACE1 promoted the K27 ubiquitination of fibronectin and regulated its secretion. Secreted fibronectin regulated ITGAV and ITGB1 expression, as well as melanoma cell adhesion and migration. Our findings disclose a novel molecular cascade involved in the regulation of fibronectin secretion, integrin expression and melanoma cell adhesion. By controlling this cascade, HACE1 displays pro-tumoural properties and is an important regulator of melanoma cell invasive properties.

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This work was supported by Institut National du Cancer (INCA) grants (2013-070 and 2013-1-MELA-04) and the “Association pour la Recherche sur le Cancer”, Equipe labellisée ARC 2015. Labex SIGNALIFE, ANR-11 LABEX-0028-01, la Ville de Nice. NEH is a recipient of “Fondation pour la Recherche Medicale” and LABEX. NH is a recipient of the ARC. We thank Dr. Emmanuel Lemichez for providing the HACE1 expression vector, Dr. Cory Hu for providing the GST-HACE1 plasmid and Pr. Alessi for providing the K27R plasmid. Frédéric Rénier, Centre Méditerranéen de Médecine Moléculaire, Bioinformatic Unit and Nicolas Nottet are supported by The Cancéropôle PACA. The authors thank the C3M animal and imaging facilities.

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  1. Edited by S. Fulda


  1. Biology and pathologies of melanocytes, Team 1, Inserm U1065, Equipe labellisée ARC 2015, C3M, Université Nice Côte d’Azur, Nice, France

    • Najla El-Hachem
    • , Nadia Habel
    • , Tanesha Naiken
    • , Hanene Bzioueche
    • , Yann Cheli
    • , Guillaume E. Beranger
    • , Emilie Jaune
    • , Florian Rouaud
    • , Frédéric Reinier
    • , Céline Gaudel
    • , Corine Bertolotto
    •  & Robert Ballotti
  2. CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Côte d’Azur, Sophia Antipolis, France

    • Nicolas Nottet
  3. Inserm U1065, Team 2, C3M, Université Nice Côte d’Azur, Nice, France

    • Pascale Colosetti


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Correspondence to Robert Ballotti.

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