USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGFß2 transcription

Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGFß2 expression by directly reducing H3K9me3 level at the TGFß2 promoter and then activates TGF-ß/Smad/ATM signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner which deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-ß/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-ß/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer. Overall design: Analysis of control and shKDM4C lung cancer cell lines obtained from 3 independent samples each.