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Oncogene (2013) 32, 13511362& 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13
http://www.nature.com/ONC
Web End =www.nature.com/onc
ORIGINAL ARTICLE
Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer
C Dong1,2, Y Wu2,3, Y Wang1,2, C Wang2,4, T Kang5, PG Rychahou2,6, Y-I Chi1, BM Evers1,2,6 and BP Zhou1,2
Expression of E-cadherin, a hallmark of epithelialmesenchymal transition (EMT), is often lost due to promoter DNA methylation in basal-like breast cancer (BLBC), which contributes to the metastatic advantage of this disease; however, the underlying mechanism remains unclear. Here, we identied that Snail interacted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major methyltransferase responsible for H3K9me3 that intimately links to DNA methylation. We demonstrated that the SNAG domain of Snail and the SET domain of Suv39H1 were required for their mutual interactions. We found that H3K9me3 and DNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We showed that Snail interacted with Suv39H1 and recruited it to the E-cadherin promoter for transcriptional repression. Knockdown of Suv39H1 restored E-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in the inhibition of cell migration, invasion and metastasis of BLBC. 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 against this disease.
Oncogene (2013) 32, 13511362; doi:http://dx.doi.org/10.1038/onc.2012.169
Web End =10.1038/onc.2012.169 ; published online 7 May 2012
Keywords: metastasis; EMT; chromatin modications; transcription; Snail
INTRODUCTIONBreast cancer is the second leading cause of cancer-related death in women with a yearly toll of 440 000 deaths in the United
States alone.1 Despite exciting progress towards understanding breast cancer development and progression, and in the development of novel therapeutic strategies, breast cancer-related deaths are primarily due to the incurable nature of metastasis. Therefore, novel therapeutic strategies are required to prevent and treat metastatic breast cancer. A better understanding of the molecular events that contribute to tumor invasion and metastasis is crucial to the development of such strategies.
The increased motility and invasiveness of metastatic tumor cells are reminiscent of the events that occur at epithelial mesenchymal transition (EMT), which is a characteristic of embryonic development, tissue remodeling, wound healing and metastasis.24 In these EMT processes, epithelial cells acquire broblast-like properties and...