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The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

Oncogene volume 38, pages 2320–2336 (2019)Cite this article

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Abstract

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin–angiotensin system (RAS) is a major physiological regulatory pathway controlling salt–water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.

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Acknowledgements

The work was supported by The Chief Scientific Officer of Scotland, The Anonymous Trust, Tenovus Scotland (to Dr. T.C.), Melanoma Focus (to C.P.), The Leng Foundation (to C.P.) and The Brain Tumour Research Campaign (to N.S.). Antonio Vega-Rioja is under contract Proyectos I + D + I para jovenes investigadores from de Economica y Competitividad (SAF2014–60649-JN) and co-funded by Fondo Europeo de Regional-FEDER. Tim Crook is a Scottish Senior Clinical Fellow in Medical Oncology.

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Author notes

  1. These authors contributed equally: Alexander Renziehausen, Andreas G. Tzakos, Nelofer Syed, Tim Crook.

Authors and Affiliations

  1. John Fulcher Neuro-Oncology Laboratory, Division of Brain Sciences, Imperial College London, London, UK

    Alexander Renziehausen, Nabil Hajji & Nelofer Syed

  2. Department of Dermatology, The First Hospital of China Medical University, Shenyang, China

    Hexiao Wang

  3. Medical Research Institute, Ninewells Hospital & Medical School, Dundee, UK

    Bhavya Rao, Lynda Weir & Charlotte Proby

  4. Department of Oncology, Ospedale San Croce e Carle, Cuneo, Italy

    Cristiana Lo Nigro, Laura Lattanzio & Marco Merlano

  5. Hospital Universitario Virgen Macarena, Sevilla, Spain

    Antonio Vega-Rioja & Maria del Carmen Fernandez-Carranco

  6. Barts and the London School of Medicine and Dentistry, London, UK

    Rubeta Matin & Catherine Harwood

  7. Royal Marsden Hospital, Fulham Road, London, UK

    Su Li

  8. Kent Oncology Centre, Maidstone Hospital, Maidstone, ME16 9QQ, UK

    Van Ren Sim

  9. Department of Neurosurgery, Charing Cross Hospital, London, UK

    Kevin O’Neill

  10. Department of Pathology, Ninewells Hospital, Dundee, UK

    Alan Evans

  11. Breast Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Alastair Thompson

  12. Department of Medical Oncology, Bart’s Cancer Centre, London, UK

    Peter Szlosarek

  13. Department of Dermatology, Ninewells Hospital, Dundee, UK

    Colin Fleming & Charlotte Proby

  14. Imperial College, London, UK

    Justin Stebbing

  15. Department of Chemistry, University of Ioannina, Ioannina, Greece

    Andreas G. Tzakos

  16. St Lukes Cancer Centre, Guildford, UK

    Tim Crook

Authors
  1. Alexander Renziehausen
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  24. Tim Crook
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Correspondence to Nelofer Syed or Tim Crook.

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Renziehausen, A., Wang, H., Rao, B. et al. The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention. Oncogene 38, 2320–2336 (2019). https://doi.org/10.1038/s41388-018-0563-y

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