Xueqin Xie1, Qiutong Wu1, Keren Zhang2, Yimin Liu1, Nana Zhang1, Qiushi Chen2, Lingyan Wang1, Wenli Li1, Jianing Zhang3, Yubo Liu4. 1. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China. 2. Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China. 3. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.. Electronic address: jnzhang@dlut.edu.cn. 4. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.. Electronic address: liuyubo@dlut.edu.cn.
Abstract
BACKGROUND: Chromatin modifier metastasis-associated protein 1 (MTA1), closely associated with tumor angiogenesis in breast cancer, plays an important role in gene expression and cancer cell behavior. Recently, an association between O-GlcNAc transferase (OGT) and MTA1 was identified by mass spectroscopy. However, the potential relationship between MTA1 and O-GlcNAc modification has not yet explored. METHODS: In the current study, the role of MTA1 and its O-GlcNAc modification in breast cancer cell genotoxic adaptation was investigated through quantitative proteomics, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome analysis, and loss- and gain-of-function experiments. RESULTS: We demonstrate that the O-GlcNAc modification promotes MTA1 to interaction with chromatin and thus changes the expression of target genes, contributing to breast cancer cell genotoxic adaptation. MTA1 is modified with O-GlcNAc residues at serine (S) residues S237/S241/S246 in adriamycin-adaptive breast cancer cells, and this modification improves the genome-wide interactions of MTA1 with gene promotor regions by enhancing its association with nucleosome remodeling and histone deacetylation (NuRD) complex. Further, O-GlcNAc modification modulates MTA1 chromatin binding, influencing the specific transcriptional regulation of genes involved in the adaptation of breast cancer cells to genotoxic stress. CONCLUSIONS: Our findings reveal a previously unrecognized role for O-GlcNAc-modified MTA1 in transcriptional regulation and suggest that the O-GlcNAc modification is a key to the molecular regulation of chemoresistance in breast cancers.
BACKGROUND: Chromatin modifier metastasis-associated protein 1 (MTA1), closely associated with tumor angiogenesis in breast cancer, plays an important role in gene expression and cancer cell behavior. Recently, an association between O-GlcNAc transferase (OGT) and MTA1 was identified by mass spectroscopy. However, the potential relationship between MTA1 and O-GlcNAc modification has not yet explored. METHODS: In the current study, the role of MTA1 and its O-GlcNAc modification in breast cancer cell genotoxic adaptation was investigated through quantitative proteomics, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome analysis, and loss- and gain-of-function experiments. RESULTS: We demonstrate that the O-GlcNAc modification promotes MTA1 to interaction with chromatin and thus changes the expression of target genes, contributing to breast cancer cell genotoxic adaptation. MTA1 is modified with O-GlcNAc residues at serine (S) residues S237/S241/S246 in adriamycin-adaptive breast cancer cells, and this modification improves the genome-wide interactions of MTA1 with gene promotor regions by enhancing its association with nucleosome remodeling and histone deacetylation (NuRD) complex. Further, O-GlcNAc modification modulates MTA1 chromatin binding, influencing the specific transcriptional regulation of genes involved in the adaptation of breast cancer cells to genotoxic stress. CONCLUSIONS: Our findings reveal a previously unrecognized role for O-GlcNAc-modified MTA1 in transcriptional regulation and suggest that the O-GlcNAc modification is a key to the molecular regulation of chemoresistance in breast cancers.