Abstract
Radioresistance is a major obstacle in successful clinical cancer radiotherapy, and the underlying mechanisms are not clear. Here we show that IKKα-mediated miR-196a biogenesis via interaction with Drosha regulates the sensitivity of nasopharyngeal carcinoma (NPC) cells to radiotherapy. Phosphorylation of IKKα at T23 site (p-IKKαT23) promotes the binding of IKKα to Drosha that accelerates the processing of miR-196a primary transcripts, leading to increased expressions of both precursor and mature miR-196a. Dephosphorylation of p-IKKαT23 downregulates miR-196a expression and promotes the resistance of NPC cells to radiation treatment. The miR-196a mimic suppresses while its inhibitor promotes the resistance of NPC to radiation treatment. Importantly, the expression of p-IKKαT23 is positively related to the expression of miR-196a in human NPC tissues, and expression of p-IKKαT23 and miR-196a is inversely correlated with NPC clinical radioresistance. Thus, our studies establish a novel mechanistic link between the inactivation of IKKαT23–Drosha–miR-196a pathway and NPC radioresistance, and de-inactivation of IKKαT23–Drosha–miR-196a pathway would be an efficient way to restore the sensitivity of radioresistant NPC to radiotherapy.
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Abbreviations
- ATM:
-
ataxia telangiectasia-mutated protein kinase
- BRCA1:
-
Breast cancer susceptibility gene 1
- CHK2:
-
Checkpoint kinase 2
- DDX5:
-
DEAD (Asp-Glu-Ala-Asp) box helicase 5
- DDX17:
-
DEAD-box helicase 17
- DHX9:
-
DEAH (Asp-Glu-Ala-His) Box Helicase 9
- DGCR8:
-
DiGeorge syndrome critical region gene 8
- EMSA:
-
electrophoretic mobility shift assay
- hnRNP A1:
-
heterogeneous nuclear ribonucleoprotein A1
- IKK:
-
IκB kinase
- IR:
-
ionizing radiation
- NF-κB:
-
nuclear factor kappa-light-chain-enhancer of activated B cells
- NPC:
-
nasopharyngeal carcinoma
- PI3K:
-
phosphoinositide 3-kinase
- RIP:
-
RNA immunoprecipitation
- Smad:
-
Sma and Mad
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Acknowledgements
We thank Dr. Xiaoli Tang and Dr. Bharat Ramratnam at Warren Alpert Medical School of Brown University for kindly providing us with GFP-Drosha plasmid. This work was supported by grants from the United States Department of Defense (W81XWH-09-1-0533) and National Institute of Health (1R01CA140956, 1R21NS073098) to J-LL, and China Nature Science Foundation (81472847, 81372905) to J-LL and XPF, by Scholarships from China Scholarship Council (CSC) to XPF and XL, and an UICC YY fellowship (Feng2014/YY1/315514) to XPF.
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Fang, X., Jeong, JH., Long, X. et al. IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy. Cell Death Differ 23, 1471–1482 (2016). https://doi.org/10.1038/cdd.2016.32
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DOI: https://doi.org/10.1038/cdd.2016.32
