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We demonstrate that epigenetic silencing of otubain 2 (OTUB2), a previously recognized oncogene, drives SSCs initiation and drug resistance. Mechanistically, OTUB2 promotes deubiquitination and phosphorylation of signal transducer and activator of transcription 1 (STAT1), then activates transcriptional regulation of calmodulin-like protein 3 (CALML3). Activation of CALML3-mediated mitochondrial calcium signaling promotes oxidative phosphorylation (OXPHOS) and glycerophospholipid synthesis, among which phosphatidylserine (PS) is the most obviously affected. Orally administered soybean-derived PS dramatically inhibits low-OTUB2-expressed SCC initiation and increased sensitivity to chemotherapy in various mouse models. Our study indicates that the OTUB2/STAT1/CALML3/PS axis plays a critical tumor-suppressive role in SCCs, clarifies the low incidence of oral and esophageal SCCs in Western countries with a high-fat diet and demonstrates the potential of food supplementation with PS as a strategy for treatment and prevention of SCCs. Overall design: RNA-seq of OTUB2 overexpressed and control KYSE150 cells after administrating phosphatidylserine"],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"Soybean derived phosphatidylserine synthetically targets OTUB2 epigenetic silencing in squamous cell carcinoma","description":"Soybean derived phosphatidylserine synthetically targets OTUB2 epigenetic silencing in squamous cell carcinoma","dates":{"last_updated":"2025-09-24","first_public":"2022-10-07"},"accession":"PRJNA721679","cross_references":{"GEO":["GSE172001"],"taxon":["9606"]}}