Nuclear translocation of nucleotide enzyme Phosphoglucomutase 2 governs DNA damage response and anti-tumor immunity
Yingying Lyu,
Chaxian Liu,
Hao Lin,
Haikun Song,
Qiyuan Zhuang,
Ankang Hu,
Liang Chen,
Hui Yang,
Ying Mao
Affiliations
Yingying Lyu
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China
Chaxian Liu
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China
Hao Lin
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China
Haikun Song
Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, PR China
Qiyuan Zhuang
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China
Ankang Hu
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China
Liang Chen
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China; National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, PR China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China; Corresponding author.
Hui Yang
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China; National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, PR China; Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, PR China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China; Corresponding author. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China.
Ying Mao
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China; National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, PR China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, PR China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China; Corresponding author.
Targeting nucleotide enzymes emerges as a promising avenue for impeding tumor proliferation and fortifying anti-tumor immunogenicity. The non-canonical role of nucleotide enzymes remains poorly understood. In this study, we have identified that Phosphoglucomutase 2 (PGM2) rapidly accumulates at the DNA damage site to govern the DNA damage response mediated by the phosphorylation at Serine 165 and by forming a complex with Rho-associated coiled-coil-containing protein kinase 2 (ROCK2). Silencing PGM2 in Glioblastoma Multiforme (GBM) cells heightens DNA damage in vitro and enhances the sensitivity of temozolomide (TMZ) treatment by activating anti-tumor immunity in vivo. Furthermore, we demonstrate that pharmacological inhibition of ROCK2 synergistically complements TMZ treatment and pembrolizumab (PD-L1) checkpoint immunotherapy, augmenting anti-tumor immunity. This study reveals the non-canonical role of the nucleotide enzyme PGM2 in the regulation of DNA damage response and anti-tumor immunity, with implications for the development of therapeutic approaches in cancer treatment.
