title: Metformin mediated reversal of epithelial to mesenchymal transition is triggered by epigenetic changes in E-cadherin promoter.
abstract: Epithelial-mesenchymal transition (EMT) is one of the key biological phenomena behind cancer and metastasis. Clinical studies suggest that patients undergoing metformin therapy are less predisposed to cancer but the underlying mechanism is far from clear. Given that metformin also acts as TGF-β inhibitor, we sought to explore whether and how metformin could modulate EMT in a cancer like microenvironment. Our data using human cell lines revealed that metformin induced a distinct change from stromal-shaped mesenchymal cells to cuboidal-shaped epithelial cells with upregulation of epithelial markers and mitigation of their invasive property. One of the key regulatory pathways, which intersect tumorigenesis and metformin activity, is AMPK. We demonstrated that metformin attenuates ERK signaling by activating AMPK pathway leading to suppression of Snail and Slug resulting in upregulation of crucial tumor suppressor gene E-cadherin. ChIP assay confirmed insufficient binding of repressors like Slug to the E-cadherin promoter. Further, our data revealed reduction in HDAC activity prompting hypomethylation of E-cadherin promoter thus reflecting an epigenetic modification. To expand the translational significance of the study we verified these findings in diabetic patients undergoing metformin treatment. To our knowledge this is the first report representing an inverse relationship of AMPK and ERK signaling axis in promoting mesenchymal to epithelial transition (MET) via re-expression of E-cadherin upon metformin treatment thus rationalizing lower incidence of cancer in metformin-administered patients.
  
  
  
  Metformin promotes reversal of the epithelial-mesenchymal transition. Metformin attenuates ERK signaling by activating AMP kinase. Metformin induces hypomethylation of the E-cadherin gene promoter. Epigenetic modification of the E-cadherin promoter was observed in leukocytes from diabetic subjects. These findings provide a potential basis for decreased cancer incidence in metformin-treated subjects.
authors.affiliation: School of Regenerative Medicine, Manipal University, Bangalore, 560 065, India.
authors.forename: Poulomi
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: School of Regenerative Medicine, Manipal University, Bangalore, 560 065, India.
authors.forename: Harshini
authors.initials: H
authors.lastname: Surendran
authors.affiliation: Functional Genomics and Gene Silencing Group, Centre for Cellular and Molecular Biology, Hyderabad, 500 007, India.
authors.forename: Debabani Roy
authors.initials: DR
authors.lastname: Chowdhury
authors.affiliation: Department of Diabetes and Endocrinology, Manipal Hospital, Bangalore, 560 017, India.
authors.forename: Karthik
authors.initials: K
authors.lastname: Prabhakar
authors.affiliation: School of Regenerative Medicine, Manipal University, Bangalore, 560 065, India. rajarshi.pal@manipal.edu.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Pal
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D015703:Antigens, CD; D001483:Base Sequence; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D006657:Histones; D007004:Hypoglycemic Agents; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D008687:Metformin; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; D006655:Histone Deacetylases
keywords: AMPK; Diabetes; E-cadherin; ERK; Epithelial-mesenchymal transition; Metformin; Methylation