Twist1 is a basic helix-loop-helix transcription factor, essential during early development in mammals. While Twist1 induces epithelial-to-mesenchymal transition (EMT), here we show that Twist1 overexpression enhances nuclear and mitotic aberrations. This is accompanied by an increase in whole chromosomal copy number gains and losses, underscoring the role of Twist1 in inducing chromosomal instability (CIN) in colorectal cancer cells. Array comparative genomic hybridization (array CGH) analysis further shows sub-chromosomal deletions, consistent with an increased frequency of DNA double strand breaks (DSBs). Remarkably, Twist1 overexpression downmodulates key cell cycle checkpoint factors—Bub1, BubR1, Mad1 and Mad2—that regulate CIN. Mathematical simulations using the RACIPE tool show a negative correlation of Twist1 with E-cadherin and BubR1. Data analyses of gene expression profiles of patient samples from The Cancer Genome Atlas (TCGA) reveal a positive correlation between Twist1 and mesenchymal genes across cancers, whereas the correlation of TWIST1 with CIN and DSB genes is cancer subtype-specific. Taken together, these studies highlight the mechanistic involvement of Twist1 in the deregulation of factors that maintain genome stability during EMT in colorectal cancer cells. Twist1 overexpression enhances genome instability in the context of EMT that further contributes to cellular heterogeneity. In addition, these studies imply that Twist1 downmodulates nuclear lamins that further alter spatiotemporal organization of the cancer genome and epigenome. Notwithstanding their genetic background, colorectal cancer cells nevertheless maintain their overall ploidy, while the downstream effects of Twist1 enhance CIN and DNA damage enriching for sub-populations of aggressive cancer cells.

中文翻译：

---

Twist1 在结直肠癌细胞中诱导染色体不稳定性 (CIN)。

Twist1 是一种基本的螺旋-环-螺旋转录因子，在哺乳动物的早期发育过程中必不可少。虽然 Twist1 诱导上皮间质转化 (EMT)，但我们在此显示 Twist1 过表达增强了核和有丝分裂畸变。这伴随着整个染色体拷贝数的增加和减少，强调了 Twist1 在诱导结直肠癌细胞染色体不稳定性 (CIN) 中的作用。阵列比较基因组杂交 (array CGH) 分析进一步显示亚染色体缺失，这与 DNA 双链断裂 (DSB) 的频率增加一致。值得注意的是，Twist1 过表达下调了调节 CIN 的关键细胞周期检查点因子——Bub1、BubR1、Mad1 和 Mad2。使用 RACIPE 工具进行的数学模拟显示 Twist1 与 E-cadherin 和 BubR1 呈负相关。来自癌症基因组图谱 (TCGA) 的患者样本基因表达谱的数据分析揭示了 Twist1 与跨癌症间充质基因之间的正相关性，而 TWIST1 与 CIN 和 DSB 基因的相关性是癌症亚型特异性的。总之，这些研究强调了 Twist1 在大肠癌细胞 EMT 期间维持基因组稳定性的因素的失调中的机制参与。Twist1 过表达增强了 EMT 环境中的基因组不稳定性，这进一步导致了细胞异质性。此外，这些研究表明 Twist1 下调核纤层蛋白，从而进一步改变癌症基因组和表观基因组的时空组织。尽管具有遗传背景，但结直肠癌细胞仍然保持其整体倍性，