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Cell Death Differ. 2018 Nov;25(11):2010-2022. doi: 10.1038/s41418-018-0090-y. Epub 2018 Mar 7.

Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells.

Author information

1
Biology and pathologies of melanocytes, Team 1, Inserm U1065, Equipe labellisée ARC 2015, C3M, Université Nice Côte d'Azur, Nice, France.
2
CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Côte d'Azur, Sophia Antipolis, France.
3
Inserm U1065, Team 2, C3M, Université Nice Côte d'Azur, Nice, France.
4
Biology and pathologies of melanocytes, Team 1, Inserm U1065, Equipe labellisée ARC 2015, C3M, Université Nice Côte d'Azur, Nice, France. ballotti@unice.fr.

Abstract

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.

PMID:
29515254
PMCID:
PMC6219503
[Available on 2019-11-01]
DOI:
10.1038/s41418-018-0090-y

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