Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition

Abstract

Epithelial-mesenchymal transition (EMT) plays pivotal roles during embryonic development and carcinoma progression. Members of the Snail family of zinc finger transcription factors are central mediators of EMT and induce EMT in part by directly repressing epithelial markers such as E-cadherin, a gatekeeper of the epithelial phenotype and a suppressor of tumor invasion. However, the molecular mechanism underlying Snai1 (Snail)-mediated transcriptional repression remains incompletely understood. Here we show that Snai1 physically interacts with and recruits the histone demethylase LSD1 (KDM1A) to epithelial gene promoters. LSD1 removes dimethylation of lysine 4 on histone H3 (H3K4m2), a covalent histone modification associated with active chromatin. Importantly, LSD1 is essential for Snai1-mediated transcriptional repression and for maintenance of the silenced state of Snai1 target genes in invasive cancer cells. In the absence of LSD1, Snai1 fails to repress E-cadherin. In cancer cells in which E-cadherin is silenced, depletion of LSD1 results in partial de-repression of epithelial genes and elevated H3K4m2 levels at the E-cadherin promoter. These results underline the critical role of LSD1 in Snai1-dependent transcriptional repression of epithelial markers and suggest that the LSD1 complex may be a potential therapeutic target for prevention of tumor invasion.

EED regulates epithelial–mesenchymal transition of cancer cells induced by TGF-β

“…The plasticity of EMT suggests that epigenetic regulation such as DNA methylation, histone modification and microRNA may be involved in EMT program [11]. There are several papers including our study demonstrating the connection between E-cadherin repression and the function of histone methyl-modifying enzymes [7,12,13]. However, the role of histone methylation in EMT is just beginning to be disclosed.…”

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

“…Previous reports linked Lsd1 with NuRD and CoREST complex to regulate EMT-related processes in cancer progression and in cell culture-based EMT assays 17,[36][37][38] . More specifically, Wang et al 17 showed that LSD1 influences the metastatic potential of breast cancer cell line MDA-MB-231.…”

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

“…8 The mechanism of E-cadherin repression by Snail1 is mediated through the recruitment of histone deacetylases (HDACs) and the corepressor SIN3A. 105 Several recent studies have shown that Snail1 also interacts with additional histone modifying enzymes (e.g., G9a, Suv39H1, EZH2, LSD1 and LOXL2) 103,[106][107][108][109] and DNA methyltransferases (DNMTs) 103 during EMT. An active E-cadherin promoter is marked by H3K4me3 and has to be first demethylated by the demethylase LSD1, 108,110 before H3K9 could be di-methylated by G9a, 103 or tri-methylated by Suv39H1, 106 to mediate repression of E-cadherin.…”