title: Methylation-regulated miR-149 modulates chemoresistance by targeting GlcNAc N-deacetylase/N-sulfotransferase-1 in human breast cancer.
abstract: 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.
authors.affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi, China.
authors.forename: Dong-Xu
authors.initials: DX
authors.lastname: He
authors.forename: Xiao-Ting
authors.initials: XT
authors.lastname: Gu
authors.forename: You-Ran
authors.initials: YR
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D020121:5' Untranslated Regions; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D006497:Heparan Sulfate; D035683:MicroRNAs; D012333:RNA, Messenger; D015238:Sulfotransferases; C551557:MIRN149 microRNA, human; C021350:heparitin sulfotransferase
keywords: GlcNAc N-deacetylase/N-sulfotransferase-1; chemoresistance; heparan sulfate; methylation; miR-149