O-GlcNAc modification regulates MTA1 transcriptional activity during breast cancer cell genotoxic adaptation

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 8; p. 129930
• Main Authors: Xie, Xueqin, Wu, Qiutong, Zhang, Keren, Liu, Yimin, Zhang, Nana, Chen, Qiushi, Wang, Lingyan, Li, Wenli, Zhang, Jianing, Liu, Yubo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2021
• Subjects: Acetylglucosamine - chemistry; Acetylglucosamine - metabolism; angiogenesis; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; breasts; Cell Proliferation; Chromatin - chemistry; Chromatin - genetics; Chromatin - metabolism; chromatin immunoprecipitation; DNA Damage; gain-of-function mutation; gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; genes; Genotoxic adaptation; histones; Humans; mass spectrometry; MTA1; mutagens; N-Acetylglucosaminyltransferases - metabolism; neoplasm cells; nucleosomes; O-GlcNAc; Prognosis; Protein Processing, Post-Translational; proteomics; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; serine; Survival Rate; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; transcription (genetics); transcriptomics; Tumor Cells, Cultured; Breast cancer; MTA1; O-GlcNAc; Genotoxic adaptation
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.129930

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. 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. 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. 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. •OGT interacts with MTA1 in breast cancer cells and promotes MTA1 O-GlcNAc modification at serine residues S237/S241/S246.•O-GlcNAc modification enhances the interaction between MTA1 and other NuRD components.•O-GlcNAc modification of MTA1 affect downstream genes expression and protect breast cancer cells against genotoxicity.