EZH2 and KDM6B Expressions Are Associated with Specific Epigenetic Signatures during EMT in Non Small Cell Lung Carcinomas.

Abstract

Simple SummaryEpithelial to Mesenchymal Transition (EMT) has been linked to multiple cancer features including invasion, metastasis, immune escape, and treatment resistance, and has therefore become a promising target mechanism for improving cancer treatment. Since it has also been described that EMT can be reversed by modulating its epigenetic regulation, our study was designed to decipher this epigenetic regulation of EMT, and more particularly its regulation by the H3K27me3 (trimethylation of lysine 27 of H3) mark and the two main enzymes which modulate it: EZH2 and KDM6B. Our results showed that these two enzymes present paradoxical roles during EMT in two cancer cell lines since both overexpression and inhibition of these two proteins led to the induction of EMT. We then identified three new target genes of EZH2 or KDM6B during EMT (INHBB, WNT5B and ADAMTS6) and demonstrated that the modulation of expression of these genes modulated the invasion capacities of the cells. These findings are therefore promising to prevent cancer cells from acquiring an invasive phenotype via the modulation of these new biomarkers of EMT regulated at the epigenetic level. The role of Epigenetics in Epithelial Mesenchymal Transition (EMT) has recently emerged. Two epigenetic enzymes with paradoxical roles have previously been associated to EMT, EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 (PRC2) Subunit), a lysine methyltranserase able to add the H3K27me3 mark, and the histone demethylase KDM6B (Lysine Demethylase 6B), which can remove the H3K27me3 mark. Nevertheless, it still remains unclear how these enzymes, with apparent opposite activities, could both promote EMT. In this study, we evaluated the function of these two enzymes using an EMT-inducible model, the lung cancer A549 cell line. ChIP-seq coupled with transcriptomic analysis showed that EZH2 and KDM6B were able to target and modulate the expression of different genes during EMT. Based on this analysis, we described INHBB, WTN5B, and ADAMTS6 as new EMT markers regulated by epigenetic modifications and directly implicated in EMT induction.