Abstract
Lung adenocarcinoma is a malignant tumor with high morbidity and mortality. ZBTB16 plays a double role in various tumors; however, the potential mechanism of ZBTB16 in the pathophysiology of lung adenocarcinoma has yet to be elucidated. We herein observed a decreased expression of ZBTB16 mRNA and protein in lung adenocarcinoma and a significantly increased DNA methylation level of ZBTB16 in patients with lung adenocarcinoma. Analysis of public databases and patients’ clinical data indicated a close association between ZBTB16 and patient survival. Ectopic expression of ZBTB16 in lung adenocarcinoma cells significantly inhibited cell proliferation, invasion, and migration. It also induced cell cycle arrest in the S phase. Meanwhile, mitotic catastrophe was induced, and DNA damage and apoptosis occurred. In line with these findings, the overexpression of ZBTB16 in xenograft mice resulted in the inhibition of tumor growth. Comprehensive analysis showed that WDHD1 was a potential target for ZBTB16. The overexpression of both isoforms of WDHD1 significantly reversed the ZBTB16-mediated inhibition of lung adenocarcinoma proliferation and cell cycle. These studies suggest that ZBTB16 impedes the progression of lung adenocarcinoma by interfering with WDHD1 transcription, making it a potential novel therapeutic target in the management of lung adenocarcinoma.
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Data availability
The RNA-seq and ChIP-seq data generated in this study were deposited in NCBI’s Gene Expression Omnibus and were accessible through GEO Series accession numbers GSE263036 and GSE263037.
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Acknowledgements
We thank all TCGA, GTEx, GEO database researchers and patients involved in the article, for their willingness to share relevant data and their contributions to medical progress. The graphical abstract is drawn by FigDraw.
Funding
This work is supported by National Natural Science Foundation of China (82102700) and Natural Science Foundation of Shandong Province (ZR2021MH192).
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Jiajun Du, Kai Wang and Deyu Guo contributed to the conception and supervision of this research. Co-authors Kai Wang, Deyu Guo, Tao Yan and Yadong Wang cultured cells, collected research materials and designed the experiment. Kai Wang, Deyu Guo, Shijie Sun, Yadong Wang, Haotian Zheng and Guanghui Wang collected patient information and conducted follow-up. Kai Wang, Deyu Guo, Tao Yan and Shijie Sun writing, review and editing this article. All the authors read and approved the final manuscript.
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Wang, K., Guo, D., Yan, T. et al. ZBTB16 inhibits DNA replication and induces cell cycle arrest by targeting WDHD1 transcription in lung adenocarcinoma. Oncogene (2024). https://doi.org/10.1038/s41388-024-03041-0
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DOI: https://doi.org/10.1038/s41388-024-03041-0