The high mobility group A2 protein epigenetically silences the Cdh1 gene during epithelial-to-mesenchymal transition.

Abstract:

:The loss of the tumour suppressor E-cadherin (Cdh1) is a key event during tumourigenesis and epithelial-mesenchymal transition (EMT). Transforming growth factor-β (TGFβ) triggers EMT by inducing the expression of non-histone chromatin protein High Mobility Group A2 (HMGA2). We have previously shown that HMGA2, together with Smads, regulate a network of EMT-transcription factors (EMT-TFs) like Snail1, Snail2, ZEB1, ZEB2 and Twist1, most of which are well-known repressors of the Cdh1 gene. In this study, we show that the Cdh1 promoter is hypermethylated and epigenetically silenced in our constitutive EMT cell model, whereby HMGA2 is ectopically expressed in mammary epithelial NMuMG cells and these cells are highly motile and invasive. Furthermore, HMGA2 remodels the chromatin to favour binding of de novo DNA methyltransferase 3A (DNMT3A) to the Cdh1 promoter. E-cadherin expression could be restored after treatment with the DNA de-methylating agent 5-aza-2'-deoxycytidine. Here, we describe a new epigenetic role for HMGA2, which follows the actions that HMGA2 initiates via the EMT-TFs, thus achieving sustained silencing of E-cadherin expression and promoting tumour cell invasion.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Tan EJ,Kahata K,Idås O,Thuault S,Heldin CH,Moustakas A

doi

10.1093/nar/gku1293

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

162-78

issue

1

eissn

0305-1048

issn

1362-4962

pii

gku1293

journal_volume

43

pub_type

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