GATA5 impedes NSCLC progression by activating SDPR and repressing CNR1 expression.
7 affiliations
- 1Chongqing University Fuling Hospital, School of Medicine, Chongqing University, Chongqing, 400044, China.
- 2Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China.
- 3Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, 400030, China.
- 4Laboratory Animal Center of Chongqing Medical University, Chongqing, 400042, China.
- 5Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
- 6Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, 400030, China. [email protected].
- 7Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, 400030, China. [email protected].
Abstract
Background
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, necessitating the identification of novel molecular mechanisms and therapeutic targets. GATA5, a member of the GATA family of transcription factors, has been implicated as a potential tumor suppressor in various malignancies; however, its role and regulatory mechanisms in NSCLC pathogenesis remain largely unexplored.Methods
GATA5 expression and promoter methylation status were assessed in NSCLC cell lines, patient tissues, and public databases using RT-PCR, western blot, methylation-specific PCR, and immunohistochemistry. Functional studies were performed using in vitro assays (proliferation, colony formation, apoptosis, migration, invasion) and in vivo xenograft models. Mechanistic insights were obtained through RNA sequencing, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments. The therapeutic potential of CNR1 inhibition was evaluated using the selective antagonist AM251 alone and in combination with cisplatin.Results
GATA5 was frequently silenced by promoter hypermethylation in NSCLC, and low GATA5 expression correlated with poor patient prognosis. Functionally, GATA5 acted as a potent tumor suppressor, inhibiting proliferation, migration, invasion, and tumor growth while promoting apoptosis. Mechanistically, GATA5 directly bound to the SDPR promoter to activate its transcription, and SDPR was identified as a critical mediator of GATA5's tumor-suppressive effects. The GATA5-SDPR axis negatively regulated CNR1, an oncogenic effector. Pharmacological inhibition of CNR1 with AM251 reversed the pro-tumorigenic effects of GATA5 loss and synergized with cisplatin to enhance anti-tumor efficacy both in vitro and in vivo.Conclusions
Our findings establish the GATA5-SDPR-CNR1 axis as a critical tumor-suppressive pathway in NSCLC. Targeting CNR1 represents a promising therapeutic strategy to overcome cisplatin resistance and improve outcomes in patients with GATA5-silenced tumors.
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BibTeX
@article{yang2026gata5,
title = {{GATA5 impedes NSCLC progression by activating SDPR and repressing CNR1 expression.}},
author = {Shuheng Yang and Jiang He and Fengsheng Dai and Chang Xu and Ling Ran and Wen Chen and Nan Li and Yu He and Wenhao Shi and Xinni Xiang and Yanchen Liu and Zhiying Zhou and Yuanyuan Tan and Tianxi Wang and Tingxiu Xiang and Yongzhong Wu},
journal = {Journal of translational medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08727-5},
url = {https://europepmc.org/article/MED/42968152},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - GATA5 impedes NSCLC progression by activating SDPR and repressing CNR1 expression.
AU - Shuheng Yang
AU - Jiang He
AU - Fengsheng Dai
AU - Chang Xu
AU - Ling Ran
AU - Wen Chen
AU - Nan Li
AU - Yu He
AU - Wenhao Shi
AU - Xinni Xiang
AU - Yanchen Liu
AU - Zhiying Zhou
AU - Yuanyuan Tan
AU - Tianxi Wang
AU - Tingxiu Xiang
AU - Yongzhong Wu
PY - 2026
DA - 2026/08/03
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08727-5
UR - https://europepmc.org/article/MED/42968152
AB - Background Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, necessitating the identification of novel molecular mechanisms and therapeutic targets. GATA5, a member of the GATA family of transcription factors, has been implicated as a potential tumor suppressor in various malignancies; however, its role and regulatory mechanisms in NSCLC pathogenesis remain largely unexplored.Methods GATA5 expression and promoter methylation status were assessed in NSCLC cell lines, patient tissues, and public databases using RT-PCR, western blot, methylation-specific PCR, and immunohistochemistry. Functional studies were performed using in vitro assays (proliferation, colony formation, apoptosis, migration, invasion) and in vivo xenograft models. Mechanistic insights were obtained through RNA sequencing, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments. The therapeutic potential of CNR1 inhibition was evaluated using the selective antagonist AM251 alone and in combination with cisplatin.Results GATA5 was frequently silenced by promoter hypermethylation in NSCLC, and low GATA5 expression correlated with poor patient prognosis. Functionally, GATA5 acted as a potent tumor suppressor, inhibiting proliferation, migration, invasion, and tumor growth while promoting apoptosis. Mechanistically, GATA5 directly bound to the SDPR promoter to activate its transcription, and SDPR was identified as a critical mediator of GATA5's tumor-suppressive effects. The GATA5-SDPR axis negatively regulated CNR1, an oncogenic effector. Pharmacological inhibition of CNR1 with AM251 reversed the pro-tumorigenic effects of GATA5 loss and synergized with cisplatin to enhance anti-tumor efficacy both in vitro and in vivo.Conclusions Our findings establish the GATA5-SDPR-CNR1 axis as a critical tumor-suppressive pathway in NSCLC. Targeting CNR1 represents a promising therapeutic strategy to overcome cisplatin resistance and improve outcomes in patients with GATA5-silenced tumors.
SN - 1479-5876
ER -