Transcriptional factor 3 binds to sirtuin 1 to activate the Wnt/β-catenin signaling in cervical cancer

Transcriptional factor 3 (TCF3, also termed E2A), first reported to exert crucial functions during lymphocyte development, has been revealed to participate in the pathogenesis of human cancers. The aim of this work was to investigate the function of TCF3 in cervical cancer (CC) and the molecular interactions. The bioinformatics prediction suggested that TCF3 was highly expressed in CC and linked to poor prognosis. Increased TCF3 expression was identified in CC cell lines, and its downregulation reduced proliferation and migration of CC cells <i>in vitro</i> as well as growth of xenograft tumors <i>in vivo</i>. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the TCF-3-related genes and genes showed differential expression between CC and normal tissues were mainly enriched in the Wnt/β-catenin pathway. TCF3 bound to sirtuin 1 (SIRT1) promoter for transcriptional activation, and SIRT1 promoted deacetylation and nuclear translocation of β-catenin in CC. SIRT1 overexpression blocked the role of TCF3 silencing and restored cell proliferation <i>in vitro</i> and tumor growth <i>in vivo</i>. Treatment with XAV-939, a β-catenin inhibitor, significantly suppressed the cell proliferation and tumor growth induced by SIRT1 overexpression. In conclusion, this study demonstrates that TCF3 augments progression of CC by activating SIRT1-mediated β-catenin signaling.

转录因子3（Transcriptional factor 3，又称E2A，以下简称TCF3）最初被报道在淋巴细胞发育过程中发挥关键功能，后续研究发现其参与人类癌症的发生发展。本研究旨在探讨TCF3在宫颈癌（Cervical cancer，以下简称CC）中的作用及其分子互作机制。生物信息学预测结果显示，TCF3在CC组织中呈高表达，且与不良预后密切相关。研究人员在CC细胞系中检测到TCF3表达上调，下调TCF3的表达可在体外（in vitro）抑制CC细胞的增殖与迁移，并在体内（in vivo）减缓异种移植瘤的生长。基因本体（Gene Ontology，GO）富集分析与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）富集分析结果表明，在CC组织与正常组织间存在差异表达的TCF3相关基因，主要富集于Wnt/β-连环蛋白（Wnt/β-catenin）信号通路。TCF3可结合沉默信息调节因子1（Sirtuin 1，以下简称SIRT1）的启动子区域以启动其转录，而SIRT1可促进CC细胞中β-连环蛋白的去乙酰化与核转位。过表达SIRT1可抵消TCF3沉默的调控作用，恢复体外细胞增殖与体内肿瘤生长能力。使用β-连环蛋白抑制剂XAV-939进行处理，可显著抑制SIRT1过表达诱导的细胞增殖与肿瘤生长。综上，本研究证实TCF3通过激活SIRT1介导的β-连环蛋白信号通路，促进CC的进展。