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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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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The authors declare that they have no conflict of interest.
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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