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

Biochim Biophys Acta Gen Subj. 2021 Aug;1865(8):129930. doi: 10.1016/j.bbagen.2021.129930. Epub 2021 May 18.

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.

Keywords: Breast cancer; Genotoxic adaptation; MTA1; O-GlcNAc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / chemistry*
  • Acetylglucosamine / metabolism
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Proliferation
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin / metabolism
  • DNA Damage*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • N-Acetylglucosaminyltransferases / metabolism
  • Prognosis
  • Protein Processing, Post-Translational*
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Survival Rate
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • Chromatin
  • Mta1 protein, human
  • Repressor Proteins
  • Trans-Activators
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • Acetylglucosamine