Conclusions
Our study linking PRKCA to radiosensitivity through a novel mechanism may enable the rational targeting of PRKCA to unlock therapeutic potentials of NSCLC.
Methods
The biologic functions of miR-4497, MED13L and PRKCA in NSCLC radiosensitivity were examined through biochemical assays including gene expression profilling, cell proliferation assay, colony formation assay, wound healing assay, transwell assay, dual luciferase reporter assay, xenograft models, immunoprecipitation, and chromatin immunoprecipitation sequencing. Clinical implications of miR-4497, MED13L and PRKCA in radiosensitivity were evaluated in NSCLC patients treated with concurrent chemoradiotherapy or radiotherapy alone.
Results
We found that radiation can trigger disassemble of Mediator complex via silencing of MED13L by miR-4497 in NSCLC. Although not interrupting structure integrity of the core Mediator or the CDK8 kinase module, suppression of MED13L attenuated their physical interactions and reduced recruitment of acetyltransferase P300 to chromatin via Mediator. Silencing of MED13L therefore diminishes global H3K27ac signals written by P300, activities of enhancer and/or promoters and expression of multiple oncogenes, especially PRKCA. Inhibition of PRKCA expression potentiates the killing effect of radiotherapy in vitro and in vivo. Remarkably, high PRKCA expression in NSCLC tissues is correlated with poor prognosis of patients received radiotherapy. Conclusions: Our study linking PRKCA to radiosensitivity through a novel mechanism may enable the rational targeting of PRKCA to unlock therapeutic potentials of NSCLC.