Chidamide alleviates TGF-β-induced epithelial–mesenchymal transition in lung cancer cell lines

Abstract

Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition is a critical process in the initiation of metastasis of various types of cancer. Chidamide is a class I histone deacetylase inhibitor with anti-tumor activity. This study investigated the effects of chidamide on TGF-β-mediated suppression of E-cadherin expression in adenocarcinomic lung epithelial cells and the molecular mechanisms involved in these effects. Western blot analysis, confocal microscopy, Quantitative methyl-specific PCR and bisulfite sequencing were used to evaluate the effects of different treatments on chidamide ameliorating TGF-β induced-E-cadherin loss. H3 acetylation binding to the promoter of E-cadherin was detected by chromatin immunoprecipitations (CHIP). We found that chidamide reduced the level of lung cancer cell migration observed using a Boyden chamber assay (as an indicator of metastatic potential). Chidamide inhibited TGF-β-induced SMAD2 phosphorylation and attenuated TGF-β-induced loss of E-cadherin expression in lung cancer cells by Western blotting and confocal microscopy, respectively. Quantitative methyl-specific PCR and bisulfite sequencing revealed that TGF-β-enhanced E-cadherin promoter methylation was ameliorated in cells treated with chidamide. We demonstrated that histone H3 deacetylation within the E-cadherin promoter was required for TGF-β-induced E-cadherin loss; cell treatment with chidamide increased the H3 acetylation detected by CHIP. Taken together, our results demonstrate that TGF-β suppressed E-cadherin expression by regulating promoter methylation and histone H3 acetylation. Chidamide significantly enhanced E-cadherin expression in TGF-β-treated cells and inhibited lung cancer cell migration. These findings indicate that chidamide has a potential therapeutic use due to its capacity to prevent cancer cell metastasis.

Engineering Lineage Potency and Plasticity of Stem Cells using Epigenetic Molecules

“…After I-CBP112 , Chidamid e was the next molecule identified to maximally increase osteogenesis and is a benzamide HD1 that inhibits Class I HDAC1, HDAC2, HDAC3 as well as Class IIb HDAC10 40 , 41 . It inhibits epithelial-mesenchymal transition (EMT) in lung cancer cell lines and increases H3 acetylation levels 41 – 43 . Chidamide ’s influence on osteogenic differentiation could possibly be through H3 acetylation based modifications, as H3 acetylation play a key role in maintaining the balance between genes associated with stem cell self-renewal and genes associated with osteogenic differentiation, for multipotent differentiation potential 44 , and increases the accessibility of osteocalcin promoter to the osteogenic transcription factors such as RUNX2.…”

Effects and mechanisms of betulinic acid on improving EGFR TKI‐resistance of lung cancer cells

“…The protocol used for western blot analysis has been described previously . Anti‐Bax (Cell signaling, 2772), anti‐BCL2 (Cell signaling, 2870), anti‐Survivin (Cell signaling, 2808), anti‐PARP (Cell signaling, 9542), anti‐p62 (GeneTex, GTX100685), anti‐LC3B (Cell signaling, 3868), anti‐TS (GeneTex, 113 289), anti‐pRb (Cell signaling, 9308S), anti‐CDK6 (GeneTex, 103 992), and anti‐β‐actin (Sigma, A5441) antibodies were detected for Bax, BCL2, Survivin, PARP, p62, LC3B, TS, pRb, CDK6, and β‐actin, respectively.…”

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…For example, retinoic acid can strengthen the anti-tumour effects of kartogenin in the blockage of the TGF-β pathway and inhibition of the viability of retinoid-resistant tumour cells [ 165 ]. Furthermore, Lin et al have found that chidamide can also attenuate the repression of E-cadherin expression caused by TGF-β, and arrest both EMT and cell migration in lung cancer [ 166 ]. Similarly, vanadium can also restrict EMT by regulating the TGF-β pathway.…”