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

Despite its canonical role in inhibiting DNA synthesis, GGH promotes tumor growth as a novel RNA‐binding protein. GGH binds GC‐rich 5′UTRs (e.g., CDC6/CCND1), recruits HuR to form a ternary complex that stabilizes mRNA via circular conformation, fueling DNA replication and the cell cycle. Targeting this axis suppresses NSCLC progression. 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. Despite its canonical role in inhibiting DNA synthesis, GGH promotes tumor growth as a novel RNA-binding protein. GGH binds GC-rich 5′UTRs (e.g., CDC6/CCND1), recruits HuR to form a ternary complex that stabilizes mRNA via circular conformation, fueling DNA replication and the cell cycle. Targeting this axis suppresses NSCLC progression. 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. Advanced Science, Volume 12, Issue 42, November 13, 2025.