Key Laboratory of Resource Biology and Biotechnology Western China, Ministry of Education; Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, 710069, China.
Department of Hematology, Provincial People's Hospital, Xi'an, 710068, China.
Cell Commun Signal. 2023 Sep 22;21(1):255. doi: 10.1186/s12964-023-01278-y.
Chemoresistance poses a significant impediment to effective treatment strategies for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our previous study unveiled that oncogene TWIST1 interacted with DNA methyltransferase 3a (DNMT3a) to regulate the decitabine (DAC) resistance in MDS/AML. However, the underlying mechanism of TWIST1 dysregulation in DAC resistance remained enigmatic. Here, we found that O-GlcNAc modification was upregulated in CD34 cells from MDS/AML patients who do not respond to DAC treatment. Functional study revealed that O-GlcNAcylation could stabilize TWIST1 by impeding its interaction with ubiquitin E3 ligase CBLC. In addition, as one typical transcription factor, TWIST1 could bind to the promoter of O-GlcNAc transferase (OGT) gene and activate its transcription. Collectively, we highlighted the crucial role of the O-GlcNAcylated TWIST1 in the chemoresistance capacity of MDS/AML clonal cells, which may pave the way for the development of a new therapeutic strategy targeting O-GlcNAcylated proteins and reducing the ratio of MDS/AML relapse. Video Abstract.
化疗耐药性是骨髓增生异常综合征（MDS）和急性髓系白血病（AML）有效治疗策略的重大障碍。我们之前的研究揭示，癌基因 TWIST1 与 DNA 甲基转移酶 3a（DNMT3a）相互作用，调节 MDS/AML 中去甲基化药物（DAC）的耐药性。然而，TWIST1 失调在 DAC 耐药性中的潜在机制仍不清楚。在这里，我们发现在对 DAC 治疗无反应的 MDS/AML 患者的 CD34 细胞中，O-GlcNAc 修饰上调。功能研究表明，O-GlcNAcylation 可以通过阻止其与泛素 E3 连接酶 CBLC 的相互作用来稳定 TWIST1。此外，作为一种典型的转录因子，TWIST1 可以结合 O-GlcNAc 转移酶（OGT）基因的启动子并激活其转录。总之，我们强调了 O-GlcNAc 化 TWIST1 在 MDS/AML 克隆细胞化疗耐药能力中的关键作用，这可能为开发针对 O-GlcNAc 化蛋白的新治疗策略和降低 MDS/AML 复发率铺平道路。视频摘要。
