Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma

Discussion Herein, we provide evidence for the first time that melanoma exhibit SL metabolism changes associated with SMS1 down-regulation, not only decreasing SM synthesis but also promoting the synthesis of GlcCer, which facilitates tumor progression in mouse melanoma models (Deng et al., 2002; Weiss et al., 2003). Interestingly, a recent study indicates the formation of an heterocomplex between SMS1 and GCS in mammalian cells, which enhances and reduces SM, and GlcCer synthesis, respectively (Hayashi et al., 2018). SMS1 downregulation may limit the formation of such a complex, promoting GlcCer synthesis in melanoma. Since de novo synthesized ceramide is the substrate of both SMS1 and GCS in the Golgi, downregulation of SMS1 likely increases the ceramide pool available for GCS to produce GlcCer. Strikingly, low SMS1 expression is associated with a worse prognosis in metastatic melanoma, suggesting that reduced SM synthesis likely contributes to melanoma progression. SMS1 down-regulation, which occurs in primary melanoma, is likely an early event in melanomagenesis. Several mutations affecting the coding sequence of SGMS1 probably contribute to the decreased SMS1 expression. In the TCGA melanoma cohort, 5 out of 16 missense mutations and 1 non-sense mutation were associated with shallow deletions. Moreover, 4 deep deletions were identified as well as 17 CpG located on the two CpG islands and their shores, the methylation of which was correlated with SGMS1 downregulation in...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research