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G9a‐induced epigenetic silencing of maspin in human claudin‐low breast tumor initiating cells
Author(s) -
Rivenbark Ashley G,
Blancafort Pilar
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.122.6
Subject(s) - maspin , cancer research , histone h3 , epigenetics , ezh2 , biology , histone methyltransferase , gene knockdown , gene silencing , dna methylation , microbiology and biotechnology , gene expression , cancer , metastasis , gene , genetics
Mammary Serine Protease Inhibitor (maspin) is a tumor suppressor gene that is silenced by epigenetic mechanisms in most breast cancer cell lines. Down‐regulation of maspin contributes to metastatic progression and is associated with poor prognosis in breast cancer. Breast cancer can be classified into distinct tumor subtypes and the claudin‐low subtype most closely resembles the mammary epithelial stem cell. We have generated a model human claudin‐low breast tumor initiating cell line by exogenous expression of the OCT4 transcription factor that displays down‐regulation of a panel of tumor suppressor genes, including maspin. In order to better understand the epigenetic mechanism by which maspin is silenced in these cells, we utilized siRNA to knock down the histone H3 lysine 9 and histone H3 lysine 27 methyltransferases (G9a and EZH2) that are responsible for gene repression. Knockdown of G9a results in increased maspin expression. However, knockdown of EZH2 did not change maspin expression. These results suggest that G9a targets maspin in claudin‐low tumor initiating cells to induce gene repression through histone H3 lysine 9 methylation and subsequent DNA methylation. Thus, modulation of this epigenetic enzyme or the histone H3 lysine 9 methylation mark in the maspin promoter could potentially restore proper gene expression of the maspin breast tumor suppressor gene.