Journal Article

NUP93 facilitates the nuclear import of SOX2 to activate G3BP1 transcription and impairs gemcitabine response in pancreatic cancer

Du, Juntong, Yue, Nanxi, Chen, Jinsuo, Xu, Chao, Chen, Yao, Yang, Zhan, Sun, Hao, Gong, Ruining, Yang, Chenxiao

2026

Overview

Gemcitabine is a cornerstone chemotherapeutic for pancreatic ductal adenocarcinoma (PDAC); however, the frequent development of resistance compromises its efficacy and poses a significant challenge to patient prognosis. Here, we report that nuclear pore protein NUP93 is upregulated in PDAC and correlates with poor patient survival. Functional studies demonstrated that NUP93 promotes PDAC cell proliferation and confers gemcitabine resistance by enhancing DNA damage repair. Mechanistically, NUP93 interacts with the transcription factor SOX2 by recognizing its nuclear localization sequence and facilitates its nuclear import. Nuclear SOX2 transcriptionally activates the key stress granule component G3BP1 by directly binding to its promoter. Subsequently, G3BP1 stabilizes the mRNA of RAD51 , a crucial homologous recombination repair factor, thereby promoting DNA damage repair and gemcitabine resistance. In vivo, disruption of the NUP93 / SOX2 / G3BP1 axis suppressed tumor growth and synergized with gemcitabine. Our findings unveil the novel NUP93 - SOX2 - G3BP1 signaling axis as a critical driver of gemcitabine resistance in PDAC, presenting a promising therapeutic target for overcoming chemoresistance.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/109 / 13/51 / 14/1 / 14/19 / 14/28 / 38/77 / 45/15 / 45/90 / 631/337/572/2102 / 631/67/1504/1713 / 631/67/395 / 631/80/389/2023 / 82/29 / Active Transport, Cell Nucleus - drug effects / Adenocarcinoma / Animals / Antibodies / Biochemistry / Biomedical and Life Sciences / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - metabolism / Carcinoma, Pancreatic Ductal - pathology / Cell Biology / Cell Culture / Cell growth / Cell Line, Tumor / Cell Nucleus - metabolism / Cell proliferation / Cell Proliferation - drug effects / Chemoresistance / Cytotoxicity / Deoxycytidine - analogs & derivatives / Deoxycytidine - pharmacology / Deoxycytidine - therapeutic use / DNA damage / DNA Helicases / DNA repair / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Gemcitabine / Gene Expression Regulation, Neoplastic - drug effects / Homologous recombination / Homologous recombination repair / Humans / Immunology / Laboratory animals / Life Sciences / Medical prognosis / Mice / Mice, Nude / Nuclear Pore Complex Proteins - genetics / Nuclear Pore Complex Proteins - metabolism / Nuclear pores / Nuclear transport / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Poly-ADP-Ribose Binding Proteins - genetics / Poly-ADP-Ribose Binding Proteins - metabolism / Proteins / RNA Helicases - genetics / RNA Helicases - metabolism / RNA Recognition Motif Proteins / SOXB1 Transcription Factors - genetics / SOXB1 Transcription Factors - metabolism / Therapeutic targets / Transcription, Genetic - drug effects