COPG1 Is a Selectively Essential Regulator of Cancer Progression and Chemoresistance via Redox Modulation and AKT Signaling

The coatomer complex has been implicated in cancer progression; however, a comprehensive pan-cancer analysis is lacking. Therefore, it is essential to identify the critical roles and essentiality of coatomer genes across pan-cancer. We systematically profiled the genetic alterations, expression patterns, prognostic relevance, and functional dependencies of all coatomer subunits across multiple cancers using more than 10,000 tumor samples from The Cancer Genome Atlas, complemented by functional perturbation data from CRISPR (n = 1178) and RNAi (n = 707) screens in DepMap. Functional validation was also performed to identify the essentiality of selectively essential coatomer genes in hepatocellular carcinoma (HCC). Gene amplification, most notably of COPB2, was the most frequent alteration and was associated with poor survival in bladder and esophageal cancers. Mutations in COPA and SEC31A also demonstrated prognostic significance in endometrial carcinoma. Expression analyses revealed broad upregulation of coatomer genes across cancer types, with COPG1 and COPB1 emerging as strong risk-associated genes (HR > 2). Integrative functional dependency analyses identified COPG1 as selectively essential in multiple cancers, and its loss was associated with increased drug sensitivity. Functional validation in hepatocellular carcinoma revealed that COPG1 knockdown impaired malignant phenotypes and reduced tumorigenicity in vivo. Mechanistically, COPG1 depletion induced Golgi disruption and ER stress, increased ROS production, and suppressed PI3K–AKT signaling, thereby sensitizing cells to sorafenib and doxorubicin. Collectively, this pan-cancer analysis reveals the context-dependent roles of coatomer subunits and identifies COPG1 as a novel oncogenic driver and potential therapeutic target in HCC, mediating chemoresistance through redox modulation and PI3K–AKT pathway inhibition.