Hypermethylation of <i>SHISA3</i> Promotes Nasopharyngeal Carcinoma Metastasis by Reducing SGSM1 Stability

Abstract

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 <i>SHISA3</i> is common and contributes to the downregulation of this gene in many types of tumors, including NPC. <i>SHISA3</i> suppressed NPC cell invasion and metastasis <i>in vitro</i> and <i>in vivo</i> 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 MAPK pathway activation. Silencing <i>SGSM1</i> abrogated the inhibitory effect of <i>SHISA3</i> on NPC cell migration and invasion. This newly identified <i>SHISA3</i>-<i>TRIM21</i>-<i>SGSM1</i> axis could be a novel therapeutic target in NPC. SIGNIFICANCE: These findings highlight the mechanism by which a newly identified tumor suppressor SHISA3 suppresses invasion and metastasis of nasopharyngeal carcinoma.