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ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment

Oncogene volume 36, pages 5695–5708 (2017)Cite this article

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Abstract

Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.

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Acknowledgements

Dr G Quash is gratefully acknowledged for critical reading of the manuscript and his contributions. We also thank Dr HG Palmer for his generous contribution. This work was supported by funds from Advanced BioDesign (MPA), the Spanish Health Ministry (Fondo de Investigaciones Sanitarias-FIS) PI1400375-Fondos FEDER, AECC-GCB15152978SOEN, Marie Curie Actions (IEF_METABOSET-627869) supported MPA.

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Author notes

  1. S Sánchez-Redondo

    Present address: 10Current address: Microenvironment and Metastasis Group at CNIO, Madrid 28029, Spain.,

Authors and Affiliations

  1. Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Oncology Program, Vall d'Hebron Research institute VHIR-Vall d'Hebron Hospital, Barcelona-UAB, Spain

    M Pérez-Alea, K McGrail, S Sánchez-Redondo, B Ferrer, V Garcia-Patos & J A Recio

  2. Anatomy Pathology Department, Vall d’Hebron Hospital, Barcelona-UAB, Spain

    B Ferrer & J Hernandez-Losa

  3. Institut de Chimie et Biochimie Moléculaire et Supramoléculaire, UMR-CNRS 5246, Université de Lyon, Université Claude Bernard-Lyon1, Villeurbanne, France

    G Fournet

  4. Ramon y Cajal University Hospital, Madrid, Spain

    J Cortés

  5. Clinical Oncology Program, Vall d’Hebron Institute of Oncology-VHIO, Vall d’Hebron Hospital, Barcelona-UAB, Spain

    J Cortés & E Muñoz

  6. Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain

    S Tenbaum

  7. Advanced BioDesign, Parc Technologique de Lyon, Woodstock - Bâtiment Cèdre 1, Saint Priest, France

    G Martin & I Ceylan

  8. Service d'Hématologie et Thérapie Cellulaire, Centre Hospitalier Universitaire La Conception, Marseille, France

    R Costello

  9. Dermatology Department, Vall d’Hebron Hospital, Barcelona-UAB, Spain

    V Garcia-Patos

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  1. M Pérez-Alea
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Pérez-Alea, M., McGrail, K., Sánchez-Redondo, S. et al. ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment. Oncogene 36, 5695–5708 (2017). https://doi.org/10.1038/onc.2017.160

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