期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1865, 期 8, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbagen.2021.129930
关键词
O-GlcNAc; MTA1; Genotoxic adaptation; Breast cancer
资金
- National Natural Science Foundation of China [31971214, 31870793]
- National Science and Technology Major Project of China [2018ZX10302205]
- Natural Science Foundation of Liaoning Province [2019-MS-042]
- Fundamental Research Funds for the Central Universities [DUT20YG130, DUT20YG116, DUT21LK19]
The study revealed that O-GlcNAc modification promotes the interaction between MTA1 and chromatin, leading to changes in the expression of target genes and contributing to genotoxic adaptation in breast cancer cells. This modification improves the genome-wide interactions of MTA1 with gene promotor regions by enhancing its association with the NuRD complex, influencing the specific transcriptional regulation of genes involved in the adaptation of breast cancer cells to genotoxic stress.
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.
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