Zeng Wei, Jiang Haixiao, Wang Ying, Wang Cunzu, Yu Bo
Medical College, Yangzhou University, Yangzhou, Jiangsu, 225000, People's Republic of China.
Department of Paediatrics, Lianyungang Third People's Hospital, Lianyungang, Jiangsu, 222000, People's Republic of China.
Neurotox Res. 2022 Jun;40(3):721-732. doi: 10.1007/s12640-022-00510-w. Epub 2022 Apr 21.
The epigenetic alteration is widely understood as the key to cancer initiation. Herein, we intended to clarify the role of transcription factor 3 (TCF3) in the development of glioma and the behind epigenetic mechanism. Through bioinformatics analysis, we identified a TCF3-DNA methyltransferase 1 (DNMT1)-secreted frizzled related protein 1 (SFRP1) axis which was differentially expressed and interacted in gliomas. More specifically, TCF3 activated DNMT1 transcription, and DNMT1 repressed SFRP1 expression. TCF3 and DNMT1 were overexpressed, while SFRP1 was downregulated in glioma. Functionally, TCF3 silencing inhibited cell proliferation and migration, and promoted apoptosis, which were reversed by DNMT1. SFRP1 inhibited the tumor supporting effects of DNMT1 on glioma cells. Moreover, TCF3 downregulation or SFRP1 overexpression inhibited tumorigenesis and enhanced apoptosis of glioma cells, while DNMT1 enhanced tumorigenesis and repressed apoptosis in tumor tissues in vivo. The Wnt pathway was a downstream effector of the TCF3-DNMT1-SFRP1 axis. Collectively, this study determined a novel therapeutic target TCF3 for glioma from the perspective of epigenetic alteration via regulation of SFRP1 expression in a DNMT1-dependent manner.
表观遗传改变被广泛认为是癌症发生的关键。在此，我们旨在阐明转录因子3（TCF3）在胶质瘤发展中的作用及其背后的表观遗传机制。通过生物信息学分析，我们鉴定出一条在胶质瘤中差异表达且相互作用的TCF3 - DNA甲基转移酶1（DNMT1）- 分泌型卷曲相关蛋白1（SFRP1）轴。更具体地说，TCF3激活DNMT1转录，而DNMT1抑制SFRP1表达。在胶质瘤中，TCF3和DNMT1过表达，而SFRP1下调。在功能上，TCF3沉默抑制细胞增殖和迁移，并促进凋亡，而DNMT1可逆转这些作用。SFRP1抑制DNMT1对胶质瘤细胞的肿瘤支持作用。此外，TCF3下调或SFRP1过表达抑制胶质瘤细胞的肿瘤发生并增强其凋亡，而DNMT1在体内肿瘤组织中增强肿瘤发生并抑制凋亡。Wnt通路是TCF3 - DNMT1 - SFRP1轴的下游效应器。总体而言，本研究从表观遗传改变的角度，通过以DNMT1依赖的方式调节SFRP1表达，确定了一种新的胶质瘤治疗靶点TCF3。
