Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells

Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia and Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain

Molecular and Clinical Sciences Research Institute, St. George’s, University of London, London SW17 0RE, UK

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Cancers 2020, 12(10), 2840; https://doi.org/10.3390/cancers12102840

Received: 19 August 2020 / Revised: 25 September 2020 / Accepted: 29 September 2020 / Published: 1 October 2020

(This article belongs to the Section Molecular Cancer Biology)

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Melanoma, the most aggressive skin cancer, accounts for the majority of deaths due to this disease. Therefore, identification of genes/proteins involved in melanoma genesis and/or progression is urgent. Mutations abrogating expression of Mahogunin Ring Finger 1 (MGRN1) in mice cause complex phenotypes with hyperpigmentation, and known MGRN1 interactors are important regulators of cell shape and movement. This suggests that MGRN1 may modulate the malignant phenotype of melanoma cells. Analysis of MGRN1-KO mouse melanocytes and melanoma cells showed that lack of MGRN1 leads to cell cycle defects and to a more differentiated, less aggressive phenotype, with increased adhesion to various matrices, decreased motility and high genomic instability. The higher aggressivity of MGRN1-expressing melanoma cells was confirmed in an in vivo mouse melanoma model and is consistent with higher survival of human melanoma patients expressing low levels of MGRN1. Therefore, MGRN1 appears an important determinant of the malignant phenotype of melanoma.

Abstract

The mouse mahoganoid mutation abrogating Mahogunin Ring Finger-1 (MGRN1) E3 ubiquitin ligase expression causes hyperpigmentation, congenital heart defects and neurodegeneration. To study the pathophysiology of MGRN1 loss, we compared Mgrn1-knockout melanocytes with genetically matched controls and melan-md1 (mahoganoid) melanocytes. MGRN1 knockout induced a more differentiated and adherent phenotype, decreased motility, increased the percentage of cells in the S phase of the cell cycle and promoted genomic instability, as shown by stronger γH2AX labelling, increased burden of DNA breaks and higher abundance of aneuploid cells. Lack of MGRN1 expression decreased the ability of melanocytes to cope with DNA breaks generated by oxidizing agents or hydroxyurea-induced replicative stress, suggesting a contribution of genomic instability to the mahoganoid phenotype. MGRN1 knockout in B16-F10 melanoma cells also augmented pigmentation, increased cell adhesion to collagen, impaired 2D and 3D motility and caused genomic instability. Tumors formed by Mgrn1-KO B16-F10 cells had lower mitotic indices, fewer Ki67-positive cells and showed a trend towards smaller size. In short-term lung colonization assays Mgrn1-KO cells showed impaired colonization potential. Moreover, lower expression of MGRN1 is significantly associated with better survival of human melanoma patients. Therefore, MGRN1 might be an important phenotypic determinant of melanoma cells. View Full-Text

Keywords: Mahogunin Ring Finger 1; melanoma; melanocytes; genomic stability; DNA damage; cell cycle

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Martínez-Vicente, I.; Abrisqueta, M.; Herraiz, C.; Sirés-Campos, J.; Castejón-Griñán, M.; Bennett, D.C.; Olivares, C.; García-Borrón, J.C.; Jiménez-Cervantes, C. Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells. Cancers 2020, 12, 2840. https://doi.org/10.3390/cancers12102840

AMA Style

Martínez-Vicente I, Abrisqueta M, Herraiz C, Sirés-Campos J, Castejón-Griñán M, Bennett DC, Olivares C, García-Borrón JC, Jiménez-Cervantes C. Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells. Cancers. 2020; 12(10):2840. https://doi.org/10.3390/cancers12102840

Chicago/Turabian Style

Martínez-Vicente, Idoya, Marta Abrisqueta, Cecilia Herraiz, Julia Sirés-Campos, María Castejón-Griñán, Dorothy C. Bennett, Conchi Olivares, Jose C. García-Borrón, and Celia Jiménez-Cervantes. 2020. "Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells" Cancers 12, no. 10: 2840. https://doi.org/10.3390/cancers12102840

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Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells

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