DNA-methylation eraser TET2 activates WTIP expression to suppress an AKT-dependent chemoresistance of gastric cancer

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-04-24 DOI:10.1016/j.neo.2025.101166

Yan Guo , Hongyang Yu , Jinyang Li , Kewei Liu , Mengyi Han , Yuxin Tang , Li Su , Xianfeng Li , Haixia Wu , Dongfeng Chen

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引用次数: 0

Abstract

Chemoresistance is one of the major causes of the failure in gastric cancer (GC) treatment and leads to poor clinical outcomes. Ten-eleven translocation (TET) 2 expression and activity are frequently reduced in solid tumors. However, whether TET2 participants in GC chemoresistance remains poorly understood. In this study, we demonstrated that the TET2 acts as a novel suppressor of GC chemoresistance. TET2 and transcription factor PATZ1 work together to promote the expression of WTIP. WTIP interacts with PP2A to inhibit the T308 phosphorylation and kinase activity of AKT, thereby suppressing stemness and chemoresistance of GC. Thus, the novel TET2-WTIP transcriptional axis, which is frequently silenced, suppresses an AKT-dependent chemoresistance of GC. TET2, combined with WTIP and AKT-pT308, can synergistically serve as a biomarker for predicting chemotherapy response in GC patients. Furthermore, we highlight that combining AKT inhibitor with chemotherapy is a promising therapeutic strategy for TET2-silenced GCs with chemoresistance in clinic.

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dna甲基化擦除剂TET2激活WTIP表达，抑制胃癌akt依赖性化疗耐药

化疗耐药是胃癌治疗失败的主要原因之一，导致临床预后不佳。10 - 11易位（TET） 2在实体瘤中的表达和活性经常降低。然而，TET2参与者是否参与GC化疗耐药仍然知之甚少。在这项研究中，我们证明了TET2是一种新的GC化学耐药抑制剂。TET2和转录因子PATZ1共同促进WTIP的表达。WTIP与PP2A相互作用，抑制AKT的T308磷酸化和激酶活性，从而抑制GC的干性和化学耐药。因此，经常被沉默的新型TET2-WTIP转录轴抑制了akt依赖性的GC化学耐药。TET2与WTIP和AKT-pT308联合可协同作为预测胃癌患者化疗反应的生物标志物。此外，我们强调AKT抑制剂联合化疗是临床上治疗tet2沉默的胃癌化疗耐药的一种有前景的治疗策略。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.