Novel Phosphatase SSU72 Drives Malignant Progression in Colorectal Cancer via PERK Thr982 Dephosphorylation Mediated Endoplasmic Reticulum Stress Inactivation.

Colorectal cancer, the third most prevalent malignancy worldwide, presents significant clinical challenges due to late-stage diagnosis, therapeutic resistance, and molecular heterogeneity. Here, we identify the phosphatase SSU72 as a catalyst of colorectal cancer progression and elucidate its mechanism. High-throughput sequencing and bioinformatics analysis revealed that SSU72 overexpression was correlated with poor prognosis and found to suppress autophagy and apoptosis. Mechanistically, proteomic, RNA sequencing and single-cell RNA analyses revealed SSU72's interaction with PERK, a key endoplasmic reticulum stress regulator. Co-immunoprecipitation, immunofluorescence, and rescue experiments demonstrated that SSU72 dephosphorylated PERK at Thr982, inactivating endoplasmic reticulum stress signaling. In vivo experimental validation confirmed that SSU72-mediated suppression of endoplasmic reticulum stress promoted tumor aggressiveness. Clinically, SSU72 serves as a novel biomarker for colorectal cancer poor prognosis, and targeting its phosphatase activity to restore endoplasmic reticulum stress represents a therapeutic strategy for SSU72-high tumors. This study uncovers SSU72's dual role: beyond its canonical functions in transcription and cell cycle regulation, it directly modulates endoplasmic reticulum stress to promote colorectal cancer malignancy. Our findings address critical deficiencies in understanding colorectal cancer heterogeneity and propose SSU72 as a prognostic biomarker and viable target for precision therapy.