Twist1 and Slug mediate H2AX-regulated epithelial-mesenchymal transition in breast cells

Abstract

The epithelial-mesenchymal transition (EMT) is thought to be essential for cancer metastasis. While chromatin remodeling is involved in EMT, which processes contribute to this remodeling remain poorly investigated. Recently, we showed that silencing or removal of the histone variant H2A.X induced mesenchymal-like characteristics, including activation of the EMT transcription factors, Slug and Zeb1 in human colon cancer cells. Here, we provide the evidence that H2A.X loss in human non-tumorigenic breast cell line MCF10A results in a robust EMT activation, as substantiated by a genome-wide expression analysis. Cells deficient for H2A.X exhibit enhanced migration and invasion, along with an activation of a set of mesenchymal genes and a concomitant repression of epithelial genes. In the breast model, the EMT-related transcription factor Twist1 cooperates with Slug to regulate EMT upon H2A.X Loss. Of interest, H2A.X expression level tightly correlates with Twist1, and to a lesser extent with Slug in the panel of human breast cancer cell lines of the NCI-60 datasets. These new findings indicate that H2A.X is involved in the EMT processes in cells of different origins but pairing with transcription factors for EMT may be tissue specific.

Downregulation of miR-22 Contributes to Epithelial-Mesenchymal Transition in Osteosarcoma by Targeting Twist1

“…Twist1 is a helix-loop-helix transcription factor that plays essential roles in osteoblasts, myoblasts, and mesodermal cells, regulating their differentiation nad migration activity (29)(30)(31)(32). Twist1 further promotes tumor cell proliferation, invasion, and resistance to cell death, in addition to enhancing EMT progression and angiogenic development (33)(34)(35). Twist1 upregulation is observed in a variety of cancer types, including OS as well as breast, bladder, gastric, and ovarian cancer (36)(37)(38)(39)(40).…”

Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

“…Another important RNA Pol II-transcribed gene mitotically bookmarked by RUNX1 and critical for maintaining cellular phenotype is histone variant H2AFX (H2AFX). Silencing H2AFX in breast epithelial cells leads to induction of EMT through activation of SNAIL2/SLUG and TWIST1 [117]. Upon inhibition of the RUNX1-CBFβ interaction, we find a decrease in H2AFX expression and a concomitant, significant increase in SNAIL2/ SLUG expression (preliminary data not shown).…”

“…Of the 413 RUNX1 bookmarked protein coding genes, TOP2A, MYC, HES1, RRAS, H2AFX, and CCND3 are representative of RNA Pol II-transcribed genes involved in phenotype maintenance and cell fate decisions (See Supplementary Table 2 for complete list). Recently, HES1 and H2AFX have been identified as regulators of breast epithelial phenotype [115][116][117]. In our ChIP-seq dataset, HES1 and H2AFX show significant fold enrichment of RUNX1 occupancy among the three populations of MCF10A cells ( Figure 6C, top panels).…”

RUNX1 mitotically bookmarks target genes that are important for the mammary epithelial-to-mesenchymal transition

“…Table 1 for complete list). Recently, HES1 and H2AFX have been identified as regulators of breast epithelial phenotype (93–95). In our ChIP-seq dataset, HES1 and H2AFX show significant fold enrichment of RUNX1 occupancy between the three populations of MCF10A cells (Fig.…”

“…Another important RNA Pol II-transcribed gene mitotically bookmarked by RUNX1 and critical for maintaining cellular phenotype is histone variant H2AFX ( H2AFX ). Silencing H2AFX in breast epithelial cells leads to induction of EMT through activation of SNAIL2/SLUG and TWIST1 (95). Upon inhibition of the RUNX1-CBF β interaction, we find a decrease in H2AFX expression and a concomitant, significant increase in SNAIL2/SLUG expression.…”