School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.
Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China.
Biochim Biophys Acta Gen Subj. 2021 Aug;1865(8):129930. doi: 10.1016/j.bbagen.2021.129930. Epub 2021 May 18.
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.
染色质修饰物转移相关蛋白 1（MTA1）与乳腺癌中的肿瘤血管生成密切相关，在基因表达和癌细胞行为中发挥重要作用。最近，通过质谱分析发现 O-连接的 N-乙酰葡萄糖胺转移酶（OGT）与 MTA1 之间存在关联。然而，MTA1 与 O-连接的 N-乙酰葡萄糖胺修饰之间的潜在关系尚未得到探索。
在本研究中，通过定量蛋白质组学、染色质免疫沉淀测序（ChIP-seq）、转录组分析和功能丧失与获得实验，研究了 MTA1 及其 O-连接的 N-乙酰葡萄糖胺修饰在乳腺癌细胞遗传毒性适应中的作用。
我们证明，O-连接的 N-乙酰葡萄糖胺修饰促进 MTA1 与染色质相互作用，从而改变靶基因的表达，促进乳腺癌细胞遗传毒性适应。阿霉素适应的乳腺癌细胞中，MTA1 在丝氨酸（S）残基 S237/S241/S246 上发生 O-连接的 N-乙酰葡萄糖胺修饰，这种修饰通过增强其与核小体重塑和组蛋白去乙酰化（NuRD）复合物的结合，提高了 MTA1 与基因启动子区域的全基因组相互作用。此外，O-连接的 N-乙酰葡萄糖胺修饰调节 MTA1 染色质结合，影响涉及乳腺癌细胞对遗传毒性应激适应的基因的特定转录调控。
我们的研究结果揭示了 O-连接的 N-乙酰葡萄糖胺修饰的 MTA1 在转录调控中的先前未知作用，并表明 O-连接的 N-乙酰葡萄糖胺修饰是乳腺癌中化学抗性分子调控的关键。
