PDF(Pubmed)
Abstract：
TWIST1 (TW) is a pro-oncogenic basic helix-loop-helix (bHLH) transcription factor and promotes the hallmark features of malignancy (e.g., cell invasion, cancer cell stemness, and treatment resistance), which contribute to poor prognoses of glioblastoma (GBM). We previously reported that specific TW dimerization motifs regulate unique cellular phenotypes in GBM. For example, the TW:E12 heterodimer increases periostin (POSTN) expression and promotes cell invasion. TW dimer-specific transcriptional regulation requires binding to the regulatory E-box consensus sequences, but alternative bHLH dimers that balance TW dimer activity in regulating pro-oncogenic TW target genes are unknown. We leveraged the ENCODE DNase I hypersensitivity data to identify E-box sites and tethered TW:E12 and TW:TW proteins to validate dimer binding to E-boxes in vitro. Subsequently, TW knockdown revealed a novel TCF4:TCF12 bHLH dimer occupying the same TW E-box site that, when expressed as a tethered TCF4:TCF12 dimer, markedly repressed POSTN expression and extended animal survival. These observations support TCF4:TCF12 as a novel dimer with tumor-suppressor activity in GBM that functions in part through displacement of and/or competitive inhibition of pro-oncogenic TW dimers at E-box sites.
摘要：
TWIST1（TW）是一种致癌的碱性螺旋-环-螺旋（bHLH）转录因子，可促进恶性肿瘤的标志特征（例如，细胞入侵，癌细胞的干细胞，和治疗抗性)，这有助于胶质母细胞瘤（GBM）的不良预后。我们先前报道了特定的TW二聚化基序调节GBM中独特的细胞表型。例如,TW:E12异二聚体增加骨膜素(POSTN)表达并促进细胞侵袭。TW二聚体特异性转录调节需要与调节E-box共有序列结合，但在调节原癌基因TW靶基因时平衡TW二聚体活性的替代bHLH二聚体是未知的。我们利用ENCODEDNA酶I超敏反应数据来鉴定E-box位点和TW:E12和TW:TW蛋白以验证二聚体与E-box的体外结合。随后，TW敲低显示一个新的TCF4:TCF12bHLH二聚体占据相同的TWE-box位点，当表示为TCF4：TCF12二聚体时，显著抑制POSTN表达和延长动物存活。这些观察结果支持TCF4:TCF12作为在GBM中具有肿瘤抑制活性的新型二聚体,其部分地通过在E-box位点置换和/或竞争性抑制原癌基因TW二聚体起作用。
