journal article·2025-11Open access

The GGH/HuR Complex Binds and Stabilizes mRNAs to Maintain Tumor Cell Cycle and DNA Replication

Yu Li, Xinrui Li, Yuhui Du, Sijie Chen, Xiaoniu He, Zhangrong Xie, Zhiqing Zhou, Huijie Zhao, Xiaofei Zeng, Guoan Chen

Advanced Science· Volume 12· Issue 42

Abstract

Abstract GGH (Gamma‐glutamyl hydrolase) is a folate metabolism enzyme that hydrolyzes intracellular polyglutamylated folates and is highly expressed in various cancers. It remains unclear whether GGH functions as an oncogene and its underlying mechanisms in tumor progression. Here, it is reported that GGH silencing inhibited the growth of lung cancer cells in vivo and in vitro. The oncogenic function of GGH relied on its non‐canonical role as a novel RNA‐binding protein, which maintained the cell cycle and DNA replication by stabilizing target mRNAs. Furthermore, GGH bound to the GC‐rich motif in the 5′ untranslated region of mRNAs, such as CDC6 and CCND1. Additionally, GGH directly interacts with HuR (Human Antigen R), a well‐characterized RNA‐binding protein critical for mRNA stability in cancer. GGH, HuR, and their mRNA targets formed a ternary complex, which may facilitate the induction of a circular mRNA conformation, potentially enhancing RNA stability. Finally, it is found that GGH is highly expressed in lung cancer tissues, and its elevated expression correlates with worse patient survival in lung cancer. This discovery offered novel insights and identified potential therapeutic targets for the prevention and treatment of lung cancer.
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Research context

OpenAlex topics: RNA modifications and cancer · RNA Research and Splicing · Cancer-related Molecular Pathways

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Critical Care Medicine Fourth People's Hospital School of Medicine Tongji University Shanghai 200434 China

Department of Human Cell Biology and Genetics Joint Laboratory of Guangdong‐Hong Kong Universities for Vascular Homeostasis and Diseases SUSTech Homeostatic Medicine Institute School of Medicine Southern University of Science and Technology Shenzhen Guangdong 518055 China

State Key Laboratory for Conservation and Utilization of Bio‐resource in Yunnan and School of Ecology and Environmental Science Yunnan University Kunming 650500 China

Shanxi Bethune Hospital Shanxi Academy of Medical Sciences Third Hospital of Shanxi Medical University Tongji Shanxi Hospital Taiyuan 030032 China

H&H Group H&H Research China Research and Innovation Center Guangzhou 510700 China

Department of Oncology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou 510120 China

National Key Laboratory for Tropical Crop Breeding Shenzhen Branch Guangdong Laboratory for Lingnan Modern Agriculture Genome Analysis Laboratory of the Ministry of Agriculture Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518120 China

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