Transketolase attenuates the chemotherapy sensitivity of glioma cells by modulating R-loop formation

• Published in: Cell reports (Cambridge) 2025-01, Vol.44 (1), p.115142, Article 115142
• Main Authors: Fu, Minjie, Zhang, Mengli, Zhang, Licheng, Feng, Yuan, Gao, Chao, Xu, Hao, Zhang, Jinsen, Zhang, Huaichao, Peng, Tianping, Chu, Youjun, Wu, Yonghe, Wang, Pu, Ye, Dan, Mao, Ying, Hua, Wei
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; chemotherapy sensitivity; CP: Cancer; Drug Resistance, Neoplasm - drug effects; Genomic Instability - drug effects; glioma; Glioma - drug therapy; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Humans; Mice; R-loops; TKT; Transketolase - genetics; Transketolase - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115142

Glioblastoma (GBM) is a highly lethal malignant brain tumor with poor survival rates, and chemoresistance poses a significant challenge to the treatment of patients with GBM. Here, we show that transketolase (TKT), a metabolic enzyme in the pentose phosphate pathway (PPP), attenuates the chemotherapy sensitivity of glioma cells in a manner independent of catalytic activity. Mechanistically, chemotherapeutic drugs can facilitate the translocation of TKT protein from the cytosol into the nucleus, where TKT physically interacts with XRN2 to regulate the resolution and removal of R-loops. Depletion of TKT leads to increased R-loop accumulation and genome instability, increasing the susceptibility of glioma cells to chemotherapy. In conclusion, our study reveals a non-metabolic function of TKT in regulating R-loop dynamics, genome instability, and chemotherapy sensitivity in gliomas. [Display omitted] •TKT attenuates the chemosensitivity in glioma independent of catalytic activity•Chemotherapeutic drugs promote TKT’s nuclear translocation in glioma cells•TKT interacts with XRN2 to regulate the resolution and removal of R-loops Fu et al. discover a non-metabolic function of TKT in gliomas. Mechanistically, TKT undergoes translocation from the cytoplasm to the nucleus following chemotherapy. Nuclear TKT interacts with XRN2 to prevent excessive R-loop accumulation, while depletion of TKT leads to increased R-loop accumulation and genome instability, potentiating chemotherapy efficacy.