DPP9 modulates RPA1 stability and temozolomide sensitivity through RFWD3 Nuclear localization in glioma.
5 affiliations
- 1Clinical and Translational Research Center, Affiliated Hospital of Nantong University & Medical School of Nantong University, Nantong, Jiangsu, 226001, China.
- 2Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
- 3Department of Clinical Medicine, Xinling College of Nantong University, Nantong, Jiangsu, 226001, China.
- 4Clinical and Translational Research Center, Affiliated Hospital of Nantong University & Medical School of Nantong University, Nantong, Jiangsu, 226001, China. [email protected].
- 5Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China. [email protected].
Abstract
Background
Temozolomide resistance is a major barrier to effective glioma treatment and is frequently associated with enhanced DNA damage repair capacity. Although DPP9 has been linked to tumor development in several malignancies, whether it contributes to glioma therapeutic resistance has not been explored.Methods
Transcriptomic datasets, glioma specimens, and genetic gain- and loss-of-function approaches were employed to characterize DPP9 expression and function. RNA sequencing, co-immunoprecipitation, subcellular fractionation, and ubiquitination analyses were conducted to define the molecular basis of DPP9-mediated effects.Results
Higher DPP9 expression was observed in glioma specimens and coincided with shorter patient survival. DPP9 depletion inhibited glioma growth and enhanced TMZ sensitivity in both cultured cells and xenograft tumors. Functional experiments support a role for altered RFWD3 localization in the association between DPP9 depletion and reduced RPA1 stability. Loss of DPP9 promoted RFWD3 redistribution to the cytoplasm, resulting in increased RPA1 ubiquitination and degradation. The reduction in RPA1 was accompanied by elevated replication stress, increased accumulation of DNA damage markers, and enhanced sensitivity to TMZ-induced genotoxic stress. Restoration of RPA1 expression attenuated these defects, indicating that RPA1 mediates a substantial portion of the cellular consequences associated with DPP9 loss.Conclusion
DPP9 contributes to glioma resistance to TMZ by sustaining RPA1-dependent DNA damage responses through regulation of the RFWD3-RPA1 axis. These results identify DPP9 as an important determinant of genome maintenance in glioma cells and nominate DPP9 as a candidate target for further investigation in TMZ-resistant glioma.
Related
- Three-dimensional in vitro models for assessing temozolomide sensitivity in glioblastoma
- Selinexor enhances temozolomide efficacy in glioblastoma through modulation of multiple resistance-associated mechanisms
- Tumor Treating Fields Enhance Temozolomide-Associated Growth Suppression in Glioblastoma Cells and Patient-Derived Organoids Through Cell-Cycle Blockade, Apoptosis, and SMAD-Associated Signaling.
- The Pregnane X Receptor (PXR) contributes to phenotypic plasticity and modulates the sensitivity to targeted therapies in melanoma
- FTO-mediated m6A regulation modulates hepatic stellate cell activation through the IGF2BP1–TRIB3 axis and mitochondrial homeostasis
BibTeX
@article{wang2026dpp9,
title = {{DPP9 modulates RPA1 stability and temozolomide sensitivity through RFWD3 Nuclear localization in glioma.}},
author = {Wei Wang and Chang Che and Feng Wang and Bing Lu and Jianfei Huang and Sujie Ni},
journal = {Cellular oncology (Dordrecht, Netherlands)},
year = {2026},
month = sep,
doi = {10.1007/s13402-026-01291-6},
url = {https://europepmc.org/article/MED/42909555},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - DPP9 modulates RPA1 stability and temozolomide sensitivity through RFWD3 Nuclear localization in glioma.
AU - Wei Wang
AU - Chang Che
AU - Feng Wang
AU - Bing Lu
AU - Jianfei Huang
AU - Sujie Ni
PY - 2026
DA - 2026/09/05
JO - Cellular oncology (Dordrecht, Netherlands)
DO - 10.1007/s13402-026-01291-6
UR - https://europepmc.org/article/MED/42909555
AB - Background Temozolomide resistance is a major barrier to effective glioma treatment and is frequently associated with enhanced DNA damage repair capacity. Although DPP9 has been linked to tumor development in several malignancies, whether it contributes to glioma therapeutic resistance has not been explored.Methods Transcriptomic datasets, glioma specimens, and genetic gain- and loss-of-function approaches were employed to characterize DPP9 expression and function. RNA sequencing, co-immunoprecipitation, subcellular fractionation, and ubiquitination analyses were conducted to define the molecular basis of DPP9-mediated effects.Results Higher DPP9 expression was observed in glioma specimens and coincided with shorter patient survival. DPP9 depletion inhibited glioma growth and enhanced TMZ sensitivity in both cultured cells and xenograft tumors. Functional experiments support a role for altered RFWD3 localization in the association between DPP9 depletion and reduced RPA1 stability. Loss of DPP9 promoted RFWD3 redistribution to the cytoplasm, resulting in increased RPA1 ubiquitination and degradation. The reduction in RPA1 was accompanied by elevated replication stress, increased accumulation of DNA damage markers, and enhanced sensitivity to TMZ-induced genotoxic stress. Restoration of RPA1 expression attenuated these defects, indicating that RPA1 mediates a substantial portion of the cellular consequences associated with DPP9 loss.Conclusion DPP9 contributes to glioma resistance to TMZ by sustaining RPA1-dependent DNA damage responses through regulation of the RFWD3-RPA1 axis. These results identify DPP9 as an important determinant of genome maintenance in glioma cells and nominate DPP9 as a candidate target for further investigation in TMZ-resistant glioma.
SN - 2211-3428
SN - 2211-3436
ER -