Sphingomyelin phosphodiesterase 3 methylation and silencing in oral squamous cell carcinoma results in increased migration and invasion and altered stress response

Abstract

Neutral sphingomyelinase 2 (nSMase2), the product of the sphingomyelin phosphodiesterase 3 (SMPD3) gene, catalyzes the hydrolysis of sphingomyelin to ceramide. Ceramide acts on various signaling pathways to influence cell proliferation, survival, and stress response. Altered levels of sphingolipids and ceramides have been reported in various cancer types, including oral squamous cell carcinoma (OSCC). OSCC patients exhibit a poor 5-year survival rate of 50%, a figure that has remained stagnant for decades. To overcome this requires a better understanding of the molecular events driving this disease. The molecular analysis of the oral cavity reported here has identified the SMPD3 promoter region as a site of frequent hypermethylation and downregulation in pre-malignant and malignant tissues as compared with healthy control tissues. While lentivirus-induced overexpression of SMPD3 in cell models of oral dysplasia and OSCC did not significantly alter proliferation, it did decrease migration and invasion and increased resistance to the epidermal growth factor receptor (EGFR) inhibitor erlotinib. These results suggest that SMPD3 downregulation is a common event in OSCC progression and may promote the spread of tumor cells.

Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma

“…SMPD3 hydrolyzes sphingomyelin from the lipid rafts to release ceramide while ASAH2 participates in the catabolism of ceramide to form sphingosines and fatty acids. Overexpression of these enzymes has been reported to potentiate stress-induced ceramide accumulation and subsequent caspase-3-directed apoptosis in certain cancers [ 24 , 25 ]. Interestingly, the survival of cluster EC3 was the highest while the survival of a cohort from cluster EC5 was the lowest ( Figure 3 b).…”

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

“…Notably, gene encoding nSMase-2 was hypermethylated and silenced in hepatic cell carcinoma, whereby gene overexpression elicited diminished cellular proliferation by 50%, and knockdown promoted tumor invasiveness and migratory capacities [ 62 ]. Hypermethylation or low expression of nSMase2-encoding gene were common events in oral squamous and renal cell carcinoma, associated with spread of tumor cells, larger tumor, higher malignancy grade, and earlier recurrence [ 70 , 71 ].…”

Engineered Lipidic Nanomaterials Inspired by Sphingomyelin Metabolism for Cancer Therapy

“…n-SMase2, encoded by SMPD3, catalyzes SM catabolism to produce the anti-tumor metabolite Cer, and is associated with early postoperative recurrence of hepatocellular carcinoma [ 115 ]. The hypermethylation or low expression of n-SMase2 is a common event in oral squamous cell carcinoma and renal cell carcinoma, and is an index of tumor cell diffusion, malignancy degree, and early recurrence [ 116 , 117 ]. Immune escape, frequently occurring in human metastatic melanoma, may also be associated with this enzyme downregulation [ 115 ].…”