Targeted suppression of metastasis regulatory transcription factor SOX2 in various cancer cell lines using a sequence-specific designer pyrrole-imidazole polyamide
Targeted suppression of metastasis regulatory transcription factor SOX2 in various cancer cell lines using a sequence-specific designer pyrrole-imidazole polyamide
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DOI：
10.1016/j.bmc.2019.115248
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发表时间：
2020-02-01
影响因子：
3.5
通讯作者：
Sugiyama, Hiroshi
中科院分区：
文献类型：
--
作者：
Malinee, Madhu;Kumar, Alok;Sugiyama, Hiroshi
转移是癌症的致命特征，其损害预后并导致大多数癌症患者的死亡。S 0X 2是一种众所周知的多能性转录因子，在细胞命运决定中起核心作用，并且在肿瘤发生和转移中作为调节因子具有重叠作用。对人工控制癌细胞中SOX 2表达及其复杂转录机制的临床有用策略的需求正在增加。N-甲基吡咯（Py）和N-甲基咪唑（Im）聚酰胺是小的可编程设计配体，其可以被预编程以选择性地识别DNA序列并控制内源基因表达。在此，我们评估了设计配体（SOX 2 i）的抗癌活性。SOX 2 i在mRNA和蛋白水平上显著改变了人癌细胞系如SW 620（结肠直肠腺癌）、MKN 45（胃腺癌）、MCF 7（乳腺癌）、U2 OS（骨肉瘤）和其他不同来源和类型的癌细胞系中SOX 2的表达。全基因组转录组分析和基于细胞的分析表明，SOX 2是一个下调的上游调节因子，改变细胞增殖，细胞周期进程，代谢和凋亡途径。在小鼠模型中的研究证实了S 0X 2 i的抗转移特性。SOX 2 i抑制与EMT和干性相关的基因的表达。此外，发现Wnt经典信号转导在S 0X 2 i处理组中下调。我们的概念验证研究支持基于DNA的可编程小分子用于控制与肿瘤发生和转移相关的关键调控因子的潜力。
Metastasis, a deadly feature of cancer, compromises the prognosis and accounts for mortality in the majority of cancer patients. SOX2, a well-known pluripotency transcription factor, plays a central role in cell fate determination and has an overlapping role as a regulatory factor in tumorigenesis and metastasis. The demand is increasing for clinically useful strategies for artificial control of SOX2 expression and its complex transcription machinery in cancer cells. N-Methylpyrrole (Py) and N-methylimidazole (Im) polyamides are small programmable designer ligands that can be pre-programmed to selectively recognize DNA sequence and control endogenous gene expression. Herein, we evaluated the anticancer activity of a designer ligand (SOX2i). SOX2i remarkably altered the expression of SOX2 at the mRNA and protein level in human cancer cell lines such as SW620 (colorectal adenocarcinoma), MKN45 (gastric adenocarcinoma), MCF7 (breast carcinoma), U2OS (osteosarcoma) and other cancer cell lines of different origin and type. Genome-wide transcriptome analysis and cell-based assays showed SOX2 to be a downregulated upstream regulator that alters cell proliferation, cell cycle progression, metabolism and apoptotic pathway. Studies in the mouse model confirmed the anti-metastatic property of SOX2i. SOX2i inhibited the expression of genes associated with EMT and stemness. Moreover, Wnt-canonical signaling was found to be downregulated in the SOX2i-treated group. Our proof-of-concept study supports the potential of DNA-based programmable small molecules for controlling the key regulatory factors associated with tumorigenesis and metastasis.