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Cellular and Molecular Biology

KDM1A, a potent and selective target, for the treatment of DNMT3A-deficient non-small cell lung cancer

British Journal of Cancer volume 131, pages 655–667 (2024)Cite this article

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Abstract

Background

DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies.

Methods

To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction.

Results

We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level.

Conclusion

Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours.

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Fig. 1: DNMT3A is mutated in cancer and knockout of DNMT3A increases the malignant phenotype of lung cancer cells.
Fig. 2: In DNMT3A-deficient cells, KDM1A inhibition exerts a synthetic lethal effect through inducing apoptosis.
Fig. 3: Gene manipulation of KDM1A mimics the selective effect of chemical KDM1A inhibitors on DNMT3A-deficient NSCLC cells.
Fig. 4: In DNMT3A-KO NSCLC subcutaneous xenograft models, KDM1A inhibition effectively suppresses cell proliferation and induces cell apoptosis.
Fig. 5: KDM1A inhibitor suppresses tumor metastasis in DNMT3A-deficient NSCLCs in vitro and in vivo.
Fig. 6: DNMT3A deficiency induces KDM1A expression by reducing promoter methylation status.
Fig. 7: Illustration showing the proposed mechanism of the synthetic lethal effect mediated by deficiency of DNMT3A and inhibition of KDM1A.

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Data availability

All data are available in the main text or the supplementary materials. All data used in the current study are available from the corresponding author by reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (82272725 to CW, 82073320 to LW), “Xingliao Talents” Programme of Liaoning Province (nos. XLYC1902008 to LW) and Natural Science Foundation of Shenyang (22-315-6-11 to LW).

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Authors and Affiliations

  1. Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Yingxi Zhao, Yonghao Zheng, Jinjiang Fu, Jiayu Zhang, Hui Shao, Shougeng Liu, Jiacheng Lai, Ruijuan Liang, Lina Jia, Wei Cui, Jingyu Yang, Chunfu Wu & Lihui Wang

  2. School of Medical Devices, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Xue Zhou

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  1. Yingxi Zhao
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Contributions

Yingxi Zhao: Conceptualisation; Writing-Original Draft; Formal analysis; Investigation; Visualisation, Data Curation. Yonghao Zheng: Data Curation; Methodology; Investigation; Formal analysis; Validation; Visualisation. Jinjiang Fu: Data Curation; Methodology; Investigation; Formal analysis. Jiayu Zhang: Data Curation. Hui Shao: Investigation. Shougeng Liu: Visualisation. Jiacheng Lai: Investigation; Xue Zhou: Data Curation; Methodology. Ruijuan Liang: Data Curation. Lina Jia: Resources; Project administration. Wei Cui: Resources; Supervision. Jingyu Yang: Resources; Project administration. Chunfu Wu: Resources; Supervision. Lihui Wang: Conceptualisation; Writing-Review & Editing; Funding acquisition; Supervision; Funding acquisition.

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Correspondence to Lihui Wang.

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Zhao, Y., Zheng, Y., Fu, J. et al. KDM1A, a potent and selective target, for the treatment of DNMT3A-deficient non-small cell lung cancer. Br J Cancer 131, 655–667 (2024). https://doi.org/10.1038/s41416-024-02772-x

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