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KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells

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Abstract

Resistance to radiotherapy is a major limitation for the successful treatment of colorectal cancer (CRC). Recently, accumulating evidence supports a critical role of epigenetic regulation in tumor cell survival upon irradiation. Lysine Demethylase 4B (KDM4B) is a histone demethylase involved in the oncogenesis of multiple human cancers but the underlying mechanisms have not been fully elucidated. Here we show that KDM4B is overexpressed in human colorectal cancer (CRC) tumors and cell lines. In CRC cells, KDM4B silencing induces spontaneous double-strand breaks (DSBs) formation and potently sensitizes tumor cells to irradiation. A putative mechanism involved suppression of Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway, which is essential for efficient repair of damaged DNA. Overexpression of STAT3 in KMD4B knockdown cells largely attenuates DNA damage triggered by KDM4B silencing and increases cell survival upon irradiation. Moreover, we find evidence that transcription factor CAMP Responsive Element Binding Protein (CREB) is a key regulator of KMD4B expression by directly binding to a conserved region in KMD4B promoter. Together, our findings illustrate the significance of CREB–KDM4B–STAT3 signaling cascade in DNA damage response, and highlight that KDM4B may potentially be a novel oncotarget for CRC radiotherapy.

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Acknowledgements

This study was supported by Natural Science Foundation of China (NSFC) 81660096.

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Authors and Affiliations

  1. Department of Anesthesiology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China

    Wei-Wu Deng, Qian Hu, Qiu-Hong Chen, Wen-Xiang Wang, Huai-Gen Zhang, Qin Zhang, Yuan-Lu Huang & Xue-Kang Zhang

  2. General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China

    Zheng-Ren Liu

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  1. Wei-Wu Deng
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Correspondence to Xue-Kang Zhang.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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11010_2018_3345_MOESM1_ESM.eps

Supplementary Figure 1. KDM4B silencing doesn’t induce cell death or proliferation arrest. Growth curves of KDM4B knockdown or control knockdown cells. 10,000 cells were cultured for up to 72 h and the number of cells overtime were calculated. Data represent the mean ± s.e.m. for three independent experiments. No significant difference was observed between groups. Supplementary material 1 (EPS 1910 KB)

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Deng, WW., Hu, Q., Liu, ZR. et al. KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells. Mol Cell Biochem 449, 81–90 (2018). https://doi.org/10.1007/s11010-018-3345-5

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  • DOI: https://doi.org/10.1007/s11010-018-3345-5

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