Hypermethylation of SHISA3 promotes nasopharyngeal carcinoma metastasis by reducing SGSM1 stability

Altered DNA methylation is a key feature of cancer, and aberrant methylation is important in nasopharyngeal carcinoma (NPC) development. However, the methylation mechanisms underlying metastasis of NPC remain unclear. Analyzing data from public databases and conducting our own experiments, we report here that promoter hypermethylation of SHISA3 is common and contributes to the downregulation of this gene in many types of tumors, including NPC. SHISA3 suppressed NPC cell invasion and metastasis in vitro and in vivo by impeding the E3 ubiquitin ligase tripartite motif containing 21 (TRIM21)-mediated ubiquitination and degradation small G protein signaling modulator 1 (SGSM1) and by inhibiting the mitogen-activated protein kinase (MAPK) pathway activation. Silencing SGSM1 abrogated the inhibitory effect of SHISA3 on NPC cell migration and invasion. This newly identified SHISA3-TRIM21-SGSM1 axis could be a novel therapeutic target in NPC.

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