Abstract Epithelial-mesenchymal transition (EMT) plays a crucial role in cancer progression and is driven by EMT–inducing transcription factors (EMT-TFs). Although core EMT-TFs are well characterized, transcription factors that couple EMT to malignant phenotypes remain incompletely defined. Here, we identified C/EBPγ as a novel inducer of EMT in lung adenocarcinoma cells by examining regions of extensive histone H3 lysine 4 trimethylation occupancy that are often a hallmark of cellular identity. Ectopic expression of C/EBPγ induced mesenchymal-like morphologies and EMT-associated gene-expression profiles, whereas its RNAi knockdown attenuated EMT. Interestingly, domain mapping showed that the leucine zipper domain, but not the DNA-binding domain, was essential for C/EBPγ-mediated EMT, indicating a novel DNA-binding-independent mechanism involving critical partner proteins. Co-immunoprecipitation and mass spectrometry identified C/EBPβ and the non-homologous end joining (NHEJ) factors XRCC5 and XRCC6 as C/EBPγ-interacting proteins. C/EBPγ promotes EMT, at least in part, by antagonizing the EMT-suppressive activity of C/EBPβ. In parallel, C/EBPγ promoted XRCC6 recruitment to etoposide-induced DNA double-strand break (DSB) sites, enhanced NHEJ activity, facilitated DSB repair, and increased survival under genotoxic stress induced by anticancer drug treatment. Collectively, these findings indicate that C/EBPγ may play a role in linking EMT-associated transcriptional changes with enhanced DNA repair capacity, which could have implications for chemoresistance in lung adenocarcinoma.
Terashima et al. (2026) studied this question.