KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells
- 37 Downloads
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.
KeywordsKDM4B STAT3 CREB Colorectal cancer DNA damage repair
This study was supported by Natural Science Foundation of China (NSFC) 81660096.
Compliance with ethical standards
Conflict of interest
The authors declare that there is no conflict of interest.
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.
- 5.Crea F, Nobili S, Paolicchi E, Perrone G, Napoli C, Landini I, Danesi R, Mini E (2011) Epigenetics and chemoresistance in colorectal cancer: an opportunity for treatment tailoring and novel therapeutic strategies. Drug Resist Updat 14:280–296. https://doi.org/10.1016/j.drup.2011.08.001 CrossRefPubMedGoogle Scholar
- 7.Fodor BD, Kubicek S, Yonezawa M, O’Sullivan RJ, Sengupta R, Perez-Burgos L, Opravil S, Mechtler K, Schotta G, Jenuwein T (2006) Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev 20:1557–1562. https://doi.org/10.1101/gad.388206 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Yang J, Jubb AM, Pike L, Buffa FM, Turley H, Baban D, Leek R, Gatter KC, Ragoussis J, Harris AL (2010) The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth. Cancer Res 70:6456–6466. https://doi.org/10.1158/0008-5472.CAN-10-0413 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Khoury-Haddad H, Guttmann-Raviv N, Ipenberg I, Huggins D, Jeyasekharan AD, Ayoub N (2014) PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair. Proc Natl Acad Sci USA 111:E728–E737. https://doi.org/10.1073/pnas.1317585111 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Marti TM, Hefner E, Feeney L, Natale V, Cleaver JE (2006) H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks. Proc Natl Acad Sci USA 103:9891–9896. https://doi.org/10.1073/pnas.0603779103 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Yang Q, Zhu Q, Lu X, Du Y, Cao L, Shen C, Hou T, Li M, Li Z, Liu C, Wu D, Xu X, Wang L, Wang H, Zhao Y, Yang Y, Zhu WG (2017) G9a coordinates with the RPA complex to promote DNA damage repair and cell survival. Proc Natl Acad Sci USA 114:E6054–E6063. https://doi.org/10.1073/pnas.1700694114 PubMedPubMedCentralGoogle Scholar