Methylation‐regulated miR‐149 modulates chemoresistance by targeting GlcNAc N‐deacetylase/N‐sulfotransferase‐1 in human breast cancer

• DOI: 10.1111/febs.13012
• Publication Date: 2014-08-23T11:37:12Z
• Authors: Dong‐Xu He; Xiao‐Ting Gu; You‐Ran Li; Li Jiang; Jian Jin; Xin Ma
• Keywords: 0303 health sciences; Antibiotics, Antineoplastic; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Breast Neoplasms; DNA Methylation; Real-Time Polymerase Chain Reaction; 3. Good health; Gene Expression Regulation, Neoplastic; Immunoenzyme Techniques; MicroRNAs; 03 medical and health sciences; Doxorubicin; Drug Resistance, Neoplasm; Tumor Cells, Cultured; Humans; Female; Heparitin Sulfate; RNA, Messenger; Sulfotransferases; 5' Untranslated Regions; Promoter Regions, Genetic; In Situ Hybridization, Fluorescence

Dysregulation of microRNA 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 GlcNAc N‐deacetylase/N‐sulfotransferase‐1 (NDST1). With downregulated miR‐149, NDST1 expression was increased in chemoresistant MCF‐7/ADM cells versus control MCF‐7 wild‐type cells. The increased NDST1 then activated a heparan sulfate‐related pathway involving activation of heparanase. Finally, expression of miR‐149 and NDST1 was confirmed in clinical chemoresistant samples of breast cancers receiving anthracycline/taxane‐based chemotherapies. The high expression of NDST1 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 NDST1.