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Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3

Oncogene volume 39, pages 6468–6479 (2020)Cite this article

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Abstract

Aberrations in epigenetic modulation dysregulate transcription, playing a critical role in the developmental process of tumors, including lung cancer. Aberrant levels of the histone 3 lysine-27 demethylase KDM6A have been found in cancer and are either positively or negatively associated with tumorigenesis and prognosis. However, the clinical relevance and functional role of KDM6A in lung cancer is largely unknown. We found that KDM6A protein expression was higher in NSCLC tissues than in the corresponding paracancer tissues and that high KDM6A expression was associated with poor patient prognosis. Furthermore, KDM6A knockdown in NSCLC cell lines markedly inhibited the tumorigenic phenotype both in vitro and in vivo. Mechanistically, KDM6A colocalized and cooperated with KMT2B to reprogram the transcriptional network via regulating the cancer pathway, in which abnormal activation of the Wnt pathway is the dominant factor. Interestingly, in NSCLC cell lines, H3K4me3 but not H3K27me2/3 or H3K4me1/2 was markedly altered upon KDM6A or KMT2B knockdown, indicating that KDM6A may act independently of H3K27 demethylases in NSCLC. Taken together, these results indicated that KDM6A or KMT2B may be a prognostic biomarker and promising therapeutic target in NSCLC.

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Fig. 1: High KDM6A expression in NSCLC was associated with poor patient prognosis.
Fig. 2: KDM6A knockdown inhibited the tumorigenic phenotype of NSCLC in vivo and in vitro.
Fig. 3: KDM6A colocalized and cooperated with KMT2B by regulating H3K4me3 to promote the tumorigenic phenotype.
Fig. 4: KDM6A cooperated with KMT2B to regulate the signaling pathways.
Fig. 5: Schematic diagram of the synergistic mechanism of KDM6A and KMT2B in NSCLC.

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Acknowledgements

We thank Drs Meiyu Geng and Jing Ai (Shanghai Institute of Materia Medica, Chinese Academy of Sciences) and other members of Dr. Meiyu Geng’s laboratory for their assistance in lab work.

Founding

This research was supported by National Natural Science Foundation of China (Grant no. 81572250).

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  1. These authors contributed equally: Xuejiao Leng, Jianfeng Wang, Na An

Authors and Affiliations

  1. Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China

    Xuejiao Leng, Na An, Xue Wang, Yile Sun & Zhiwei Chen

  2. Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Jianfeng Wang

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Contributions

XJL performed experiments and wrote the main manuscript. NA collected tumor samples and the clinical data. JFW was responsible for all statistical analysis. XW and YLS checked relevant documents. ZWC designed this study and directed the overall project. All authors reviewed the manuscript.

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Correspondence to Zhiwei Chen.

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Leng, X., Wang, J., An, N. et al. Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3. Oncogene 39, 6468–6479 (2020). https://doi.org/10.1038/s41388-020-01449-y

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