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ZBTB16 inhibits DNA replication and induces cell cycle arrest by targeting WDHD1 transcription in lung adenocarcinoma

Oncogene (2024)Cite this article

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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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Fig. 1: Differentially expressed E3 ubiquitin ligases in lung adenocarcinoma, down-regulation of ZBTB16 in lung adenocarcinoma and its correlation with prognosis.
Fig. 2: Methylation-specific PCR (MSP) results show methylation levels of ZBTB16 promoter in clinical tissues and cell lines.
Fig. 3: ZBTB16 inhibits the proliferation, DNA replication and cell division of lung adenocarcinoma cells.
Fig. 4: ZBTB16 induces cell cycle arrest and promotes the mitotic catastrophe of lung adenocarcinoma cells.
Fig. 5: ZBTB16 induces DNA damage, promotes cell apoptosis, and inhibits migration and invasion of lung adenocarcinoma cells.
Fig. 6: The Label-free quantitative proteomic results showed the ZBTB16 interacting proteins and the distribution of ZBTB16 in the nucleus/cytoplasm.
Fig. 7: The results of ChIP-seq combined with RNA-seq and public database data show that WDHD1 is the target of ZBTB16, and overexpression of ZBTB16 inhibits tumorigenicity of lung adenocarcinoma cells.
Fig. 8: Two WDHD1 isoforms overexpression reverses the function of ZBTB16 in lung adenocarcinoma cells.

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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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  1. These authors contributed equally: Kai Wang, Deyu Guo.

Authors and Affiliations

  1. Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, China

    Kai Wang, Deyu Guo, Yadong Wang, Haotian Zheng, Guanghui Wang & Jiajun Du

  2. Department of Healthcare Respiratory Medicine, Shandong Provincial Hospital, Shandong University, Jinan, China

    Kai Wang

  3. Lung Transplantation Center, Department of Thoracic Surgery, Nanjing Medical University Affiliated Wuxi People’s Hospital, Wuxi, China

    Tao Yan

  4. Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

    Shijie Sun

  5. Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China

    Guanghui Wang & Jiajun Du

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Contributions

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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Correspondence to Jiajun Du.

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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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