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Methylation‐regulated miR‐149 modulates chemoresistance by targeting Glc NA c N ‐deacetylase/ N ‐sulfotransferase‐1 in human breast cancer
Author(s) -
He DongXu,
Gu XiaoTing,
Li YouRan,
Jiang Li,
Jin Jian,
Ma Xin
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13012
Subject(s) - cancer research , microrna , heparanase , downregulation and upregulation , breast cancer , methylation , cancer , dna methylation , chemistry , biology , medicine , gene expression , metastasis , gene , biochemistry
Dysregulation of micro RNA is strongly implicated in the chemoresistance of cancer. In this study, we found that miR‐149 was downregulated and involved in chemoresistance in adriamycin ( ADM )‐resistant human breast cancer cells ( MCF ‐7/ ADM ). Downregulation of miR‐149 was related to hypermethylation of its 5′‐ UTR ; this methylation also affected the expression of the glypican 1 gene, which is both the host and the target gene of miR‐149. Furthermore, we found that miR‐149 modulated chemoresistance through targeting the expression of Glc NA c N ‐deacetylase/ N ‐sulfotransferase‐1 ( NDST 1). With downregulated miR‐149, NDST 1 expression was increased in chemoresistant MCF ‐7/ ADM cells versus control MCF ‐7 wild‐type cells. The increased NDST 1 then activated a heparan sulfate‐related pathway involving activation of heparanase. Finally, expression of miR‐149 and NDST 1 was confirmed in clinical chemoresistant samples of breast cancers receiving anthracycline/taxane‐based chemotherapies. The high expression of NDST 1 was also an unfavorable predictor for distant relapse‐free survival in Her2 and basal breast cancers. Taken together, our findings demonstrate that miR‐149 is regulated by methylation, and is a modulator of cancer chemoresistance by targeting NDST 1 .