1. KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells
- Author
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Qian Hu, Wen-Xiang Wang, Zheng-Ren Liu, Qin Zhang, Wei-Wu Deng, Huai-Gen Zhang, Xue-Kang Zhang, Yuan-Lu Huang, and Qiu-Hong Chen
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,CAMP Responsive Element Binding Protein ,Jumonji Domain-Containing Histone Demethylases ,DNA damage ,Clinical Biochemistry ,medicine.disease_cause ,CREB ,Radiation Tolerance ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,DNA Breaks, Double-Stranded ,Epigenetics ,Cyclic AMP Response Element-Binding Protein ,Molecular Biology ,Transcription factor ,biology ,Chemistry ,Cell Biology ,General Medicine ,Neoplasm Proteins ,030104 developmental biology ,Histone ,Gamma Rays ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Demethylase ,Colorectal Neoplasms ,Carcinogenesis ,Signal Transduction - 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.
- Published
- 2018