Tri-methylation of H3K79 is decreased in TGF-β1-induced epithelial-to-mesenchymal transition in lung cancer

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0380-0) contains supplementary material, which is available to authorized users.

The role of DOT1L in the proliferation and prognosis of gastric cancer

“…For in vitro study, we blocked the expression of DOT1L in GC cells by transfection, and found that the proliferation ability of the cells was significantly decreased. It was previously reported that DOT1L inhibition in ovarian cancer and lung cancer may result in cell cycle G 1 inhibition and the association of DOT1L with DNA replication [12,19]. By examining the cell cycle, we found that the G 1 phase of GC cells was stagnant, thus causing cell proliferation to slow down.…”

“…In addition, the vital functioning of DOT1L in the mixed lineage leukemia (MLL)-rearranged leukemia has been shown [8], and thus DOT1L-targeted inhibitors have been used in rearranged leukemia [9]. In solid tumors, DOT1L is also involved in its progression, such as breast cancer [10], ovarian cancer [11], and lung cancer [12]. However, to date, the therapeutic value and the prognostic impact of DOT1L in GC has not been evaluated.…”

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

“…There have been numerous reports in the past stating the significance of cadherin switching in progression and malignancy of BCa pointing to the importance of elucidating the mechanism for targeted therapy (32)(33)(34)(35)(36)(37). Moreover, it was already shown that NRP2 and E-Cadherin expression are connected in multiple cancer types (23,(38)(39)(40)(41). However, unlike the positive correlation in our model system, all publications reported a negative correlation.…”

The MYC oncogene is a global regulator of the immune response

“…BETi can inhibit MYC function and also lead to reduced expression of PD-L1. 44, [71][72][73][74][75] BETi can result in decreased MYC expression but also can block the ability of MYC to mediate gene amplification. 76,77 Therefore, BETi could have influence on MYC function through multiple mechanisms.…”

“…75 The BET inhibitor PFI-1 reduced PD-L1 levels in lung cancer. 72 The BETi OTX015 reduces PD-L1 expression in stromal cells. 73 The BETi iBET151 reduces PD-L1 and also inhibits the NF-kB family through inhibitor of kB as well as MYC.…”