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Targeted suppression of metastasis regulatory transcription factor SOX2 in various cancer cell lines using a sequence-specific designer pyrrole-imidazole polyamide.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.bmc.2019.115248 Madhu Malinee 1 , Alok Kumar 2 , Takuya Hidaka 3 , Masanobu Horie 4 , Kouichi Hasegawa 5 , Ganesh N Pandian 5 , Hiroshi Sugiyama 3
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.bmc.2019.115248 Madhu Malinee 1 , Alok Kumar 2 , Takuya Hidaka 3 , Masanobu Horie 4 , Kouichi Hasegawa 5 , Ganesh N Pandian 5 , Hiroshi Sugiyama 3
Affiliation
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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.
中文翻译：
使用序列特异性设计者吡咯-咪唑聚酰胺可靶向抑制各种癌细胞系中的转移调节转录因子SOX2。
转移是癌症的致命特征，它会影响大多数癌症患者的预后并导致死亡。SOX2是一种众所周知的多能性转录因子，在细胞命运确定中起着核心作用，并且在肿瘤发生和转移中作为调节因子具有重叠的作用。人工控制癌细胞中SOX2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，可以预先编程以选择性识别DNA序列并控制内源基因表达。本文中，我们评估了设计配体（SOX2i）的抗癌活性。SOX2i显着改变了人类癌细胞系（例如SW620（结直肠腺癌），MKN45（胃腺癌），MCF7（乳腺癌），U2OS（骨肉瘤）和其他来源不同的癌细胞）中mRNA和蛋白质水平上SOX2的表达。和类型。全基因组转录组分析和基于细胞的分析表明，SOX2是一种下调的上游调节因子，可改变细胞增殖，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SOX2i的抗转移特性。SOX2i抑制了与EMT和干性相关的基因的表达。此外，发现在SOX2i治疗组中Wnt规范信号被下调。
更新日期：2019-12-07
中文翻译：
使用序列特异性设计者吡咯-咪唑聚酰胺可靶向抑制各种癌细胞系中的转移调节转录因子SOX2。
转移是癌症的致命特征，它会影响大多数癌症患者的预后并导致死亡。SOX2是一种众所周知的多能性转录因子，在细胞命运确定中起着核心作用，并且在肿瘤发生和转移中作为调节因子具有重叠的作用。人工控制癌细胞中SOX2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，可以预先编程以选择性识别DNA序列并控制内源基因表达。本文中，我们评估了设计配体（SOX2i）的抗癌活性。SOX2i显着改变了人类癌细胞系（例如SW620（结直肠腺癌），MKN45（胃腺癌），MCF7（乳腺癌），U2OS（骨肉瘤）和其他来源不同的癌细胞）中mRNA和蛋白质水平上SOX2的表达。和类型。全基因组转录组分析和基于细胞的分析表明，SOX2是一种下调的上游调节因子，可改变细胞增殖，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SOX2i的抗转移特性。SOX2i抑制了与EMT和干性相关的基因的表达。此外，发现在SOX2i治疗组中Wnt规范信号被下调。
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