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Published on: August 9, 2013
A viral-host redox axis: EBNA1-FOSL2-ALDH3A1 defines a targetable vulnerability in EBV-positive carcinomas
Qian Liu1, Binliang Liu2, Zhenbao Liu3
1Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China; Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Basic Medical Science, Central South University, Changsha, Hunan, 410078, PR China.
Abstract:
Epstein-Barr virus (EBV)-associated carcinomas exhibit reprogrammed redox metabolism, yet the underlying regulatory network and potential metabolic vulnerabilities remain incompletely defined. Here we identify a viral-host transcriptional axis in which EBV EBNA1 induces the transcription factor FOSL2 to repress ALDH3A1. Restoration of ALDH3A1 in EBV-positive models disrupts NAD(P)H/NAD(P)+ homeostasis, inducing reductive stress. This reductive milieu upregulates GSNOR and TrxR1, potentiating the denitrosylation of GSK3β, leading to its stabilization and suppression of the Wnt/β-catenin pathway. We establish that S-nitrosylation at GSK3β Cys199 controls its stability, providing a mechanistic bridge from redox regulation to Wnt inhibition. Critically, ALDH3A1 elevation selectively curbs EBV-positive tumor growth, exploiting an infection-specific vulnerability in redox signaling. Thus, our findings integrate EBV-driven redox remodeling with Wnt/β-catenin signaling activation and propose ALDH3A1 induction as a promising therapeutic strategy for EBV-associated carcinomas.
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