Abstract 3428: The role of methylthioadenosine phosphorylase in melanoma

Methylthioadenosine phosphorylase (MTAP) is an enzyme that is expressed in virtually all normal tissues but lost in many cancers. MTAP deficiency can be due to either deletion of the MTAP gene or methylation of the MTAP promoter. In normal cells, MTAP catalyzes the conversion of methylthioadenosine (MTA), produced during polyamine biosynthesis, to adenine and 5-methylthioribose-1-phosphate, which is subsequently converted to methionine. Although recent genome wide association studies (GWAS) have associated the MTAP locus with melanoma risk, the molecular mechanisms linking MTAP loss to increased tumorigenesis are not yet fully understood. In this study, we hypothesized that loss of MTAP and the resulting accumulation of MTA would have an effect on microphthalmia transcription factor (MITF), the master regulator of melanocytes that has been shown to be an oncogene in melanoma. We present a novel signaling mechanism in which loss of MTAP and subsequent accumulation of MTA induces expression of MITF via inhibition of the phosphodiesterase PDE4D3 by MTA. Inhibition of PKA abolishes the induction of MITF, suggesting that the PKA pathway is hyperactivated when MTAP levels are low. We show that downregulation of MTAP expression leads to increased proliferation of melanoma cells. Using a melanoma xenograft mouse model, we observed that downregulation of MTAP expression leads to increased tumor growth in vivo. These data all point to MTAP as a tumor suppressor in melanoma, and indicate that MTAP loss is an alternative mechanism of dysregulating MITF, a known oncogene in melanoma. Citation Format: Jennifer Jia-An Hsiao, Pedro Andreu-Perez, Miroslav Hejna, Lajos V. Kemény, Jun Song, David E. Fisher. The role of methylthioadenosine phosphorylase in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3428.