G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer
Chenfang Dong, … , B. Mark Evers, Binhua P. Zhou
Chenfang Dong, … , B. Mark Evers, Binhua P. Zhou
Published March 12, 2012
Citation Information: J Clin Invest. 2012;122(4):1469-1486. https://doi.org/10.1172/JCI57349.
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G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer

Abstract

Breast cancers are highly heterogeneous but can be grouped into subtypes based on several criteria, including level of expression of certain markers. Claudin-low breast cancer (CLBC) is associated with early metastasis and resistance to chemotherapy, while gene profiling indicates it is characterized by the expression of markers of epithelial-mesenchymal transition (EMT) — a phenotypic conversion linked with metastasis. Although the epigenetic program controlling the phenotypic and cellular plasticity of EMT remains unclear, one contributor may be methylation of the E-cadherin promoter, resulting in decreased E-cadherin expression, a hallmark of EMT. Indeed, reduced E-cadherin often occurs in CLBC and may contribute to the early metastasis and poor patient survival associated with this disease. Here, we have determined that methylation of histone H3 on lysine 9 (H3K9me2) is critical for promoter DNA methylation of E-cadherin in three TGF-β–induced EMT model cell lines, as well as in CLBC cell lines. Further, Snail interacted with G9a, a major euchromatin methyltransferase responsible for H3K9me2, and recruited G9a and DNA methyltransferases to the E-cadherin promoter for DNA methylation. Knockdown of G9a restored E-cadherin expression by suppressing H3K9me2 and blocking DNA methylation. This resulted in inhibition of cell migration and invasion in vitro and suppression of tumor growth and lung colonization in in vivo models of CLBC metastasis. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT but also paves a way for the development of new treatment strategies for CLBC.

Authors

Chenfang Dong, Yadi Wu, Jun Yao, Yifan Wang, Yinhua Yu, Piotr G. Rychahou, B. Mark Evers, Binhua P. Zhou

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Figure 9

Knockdown of G9a expression suppresses breast tumor growth and lung colonization in vivo.

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Knockdown of G9a expression suppresses breast tumor growth and lung colo...
(A) MDA-MB231 cells stably expressing control vector or G9a shRNA were injected into the mammary fat pad of ICR-SCID mice. The growth of breast tumors was monitored every 3 days. After 9 weeks, the size of tumors from each group was recorded by using bioluminescence imaging and quantified by measuring photon flux. Values are the mean of 6 animals ± SEM. (B) Cells from A were also injected into the tail vein of ICR-SCID mice. After 9 weeks, the development of lung metastases was recorded using bioluminescence imaging and quantified by measuring photon flux (mean of 6 animals ± SEM). Results for 3 representative mice from each group are shown. Mice were sacrificed, and lung metastatic nodules were examined macroscopically or detected in paraffin-embedded sections stained with H&E. Scale bars: 100 μm. Arrowheads indicate lung metastases.