Epigenetic silencing of genes enhanced by collective role of reactive oxygen species and MAPK signaling downstream ERK/Snail axis: Ectopic application of hydrogen peroxide repress CDH1 gene by enhanced DNA methyltransferase activity in human breast cancer

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2019-06, Vol.1865 (6), p.1651-1665
• Main Authors: Pradhan, Nibedita, Parbin, Sabnam, Kar, Swayamsiddha, Das, Laxmidhar, Kirtana, R., Suma Seshadri, G., Sengupta, Dipta, Deb, Moonmoon, Kausar, Chahat, Patra, Samir Kumar
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Antioxidants - pharmacology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Butadienes - pharmacology; Cadherins - deficiency; Cadherins - genetics; Cell Line; DNA (Cytosine-5-)-Methyltransferase 1 - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA Methylation; DNMT1; E-cadherin; Epigenetics; Epithelial-Mesenchymal Transition - drug effects; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Histone modification; Histones - genetics; Histones - metabolism; Humans; Hydrogen Peroxide - antagonists & inhibitors; Hydrogen Peroxide - pharmacology; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Kaplan-Meier Estimate; MCF-7 Cells; Nitriles - pharmacology; Pentacyclic Triterpenes - pharmacology; Reactive oxygen species; Signal Transduction; Sitosterols - pharmacology; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.04.002

Loss of E-cadherin and epithelial to mesenchymal transition (EMT) are key steps in cancer progression. Reactive oxygen species (ROS) play significant roles in cellular physiology and homeostasis. Roles of E-cadherin (CDH1), EMT and ROS are intriguingly illustrated in many cancers without focusing their collective concert during cancer progression. We report that hydrogen peroxide (H2O2) treatment modulate CDH1 gene expression by epigenetic modification(s). Sublethal dosage of H2O2 treatment decrease E-cadherin, increase DNMT1, HDAC1, Snail, Slug and enrich H3K9me3 and H3K27me3 in the CDH1 promoter. The effect of H2O2 was attenuated by ROS scavengers; NAC, lupeol and beta-sitosterol. DNMT inhibitor, AZA prevented the H2O2 induced promoter-CpG-island methylation of CDH1. Treatment of cells with U0126 (inhibitor of ERK) reduced the expression of DNMT1, Snail and Slug, increased CDH1. This implicates that CDH1 is synergistically repressed by histone methylation, DNA methylation and histone deacetylation mediated chromatin remodelling and activation of Snail and Slug through ERK pathway. Increased ROS leads to activation of epigenetic machineries and EMT activators Snail/Slug which in their course of action inactivates CDH1 gene and lack of E-cadherin protein promotes EMT in breast cancer cells. ROS and ERK signaling facilitate epigenetic silencing and support the fact that subtle increase of ROS above basal level act as key cell signaling molecules. Free radical scavengers, lupeol and beta-sitosterol may be tested for therapeutic intervention of breast cancer. This work broadens the amplitude of epigenome and open avenues for investigations on conjoint effects of canonical and intrinsic metabolite signaling and epigenetic modulations in cancer. •DNA methylation of genes is augmented by ROS through enhanced expression of DNMTs and HDACs along with EMT factors Snail and Slug in breast cancer.•Tumor suppressor, CDH1 is repressed by concerted functions of ROS, activation of ERK/Snail signaling axis and methyl modification of chromatin.•Inhibition of ERK axis or scavenging of the ROS reverses the molecular profile and cellular morphology induced by external application of H2O2