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KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells
- Source :
- Molecular and Cellular Biochemistry. 449:81-90
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
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.
- 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
Subjects
Details
- ISSN :
- 15734919 and 03008177
- Volume :
- 449
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biochemistry
- Accession number :
- edsair.doi.dedup.....bea89ab63ce8d7b68c1ecb597bd6ece7