Abstract
BackgroundThe epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-β1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT.ResultsLoss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-β1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD-L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-β1-induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-β1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF-β1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin.ConclusionHistone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses.
Highlights
The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment
TGF-β1 exposure induces EMT in non-small cell lung cancer (NSCLC) cell lines A549 and H358 NSCLC cell lines were selected for EMT induction by TGF-β1 because of their previous characterization in a ZEB1-induced EMT model [25]
H3K79me3 in human normal tissues and cancers Since H3K79me3 was decreased during EMT in cancer cell lines suggesting a relation with aggressiveness, we investigated the presence of H3K79me3 in lung cancers by immunohistochemistry on two commercial tissue microarray (TMA)
Summary
The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment This process involves epigenetic reprogramming for gene expression. The epithelial-to-mesenchymal transition (EMT) is a highly dynamic and reversible mechanism by which epithelial cells can convert into a mesenchymal phenotype, allowing a loss of cellular adhesion, cellular polarity, and an improvement in migratory and invasive properties. This process occurs during embryonic development, wound healing, and metastatic expansion [1,2,3]. Each histone can be affected by post-translational modifications (PTMs), including acetylation, methylation, phosphorylation, ubiquitination or sumoylation, that define
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