Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca Morelos 62250, Mexico.
Departamento de Fisicoquímica, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
Open Biol. 2020 Jun;10(6):200050. doi: 10.1098/rsob.200050. Epub 2020 Jun 17.
Disruption of the enzymatic activities of the transcription factor TFIIH by the small molecules Triptolide (TPL) or THZ1 could be used against cancer. Here, we used the MCF10A-ErSrc oncogenesis model to compare the effect of TFIIH inhibitors between transformed cells and their progenitors. We report that tumour cells exhibited highly increased sensitivity to TPL or THZ1 and that the combination of both had a synergic effect. TPL affects the interaction between XPB and p52, causing a reduction in the levels of XPB, p52 and p8, but not other TFIIH subunits. RNA-Seq and RNAPII-ChIP-Seq experiments showed that although the levels of many transcripts were reduced, the levels of a significant number were increased after TPL treatment, with maintained or increased RNAPII promoter occupancy. A significant number of these genes encode for factors that have been related to tumour growth and metastasis, suggesting that transformed cells might rapidly develop resistance to TPL/THZ inhibitors. Some of these genes were also overexpressed in response to THZ1, of which depletion enhances the toxicity of TPL, and are possible new targets against cancer.
小分子雷公藤红素（TPL）或 THZ1 破坏转录因子 TFIIH 的酶活性可用于抗癌。在这里，我们使用 MCF10A-ErSrc 致癌模型比较了转化细胞及其前体细胞中 TFIIH 抑制剂的作用。我们报告说，肿瘤细胞对 TPL 或 THZ1 表现出高度的敏感性，并且两者的组合具有协同作用。TPL 影响 XPB 和 p52 之间的相互作用，导致 XPB、p52 和 p8 的水平降低，但其他 TFIIH 亚基不受影响。RNA-Seq 和 RNAPII-ChIP-Seq 实验表明，尽管许多转录本的水平降低，但在 TPL 处理后，大量转录本的水平增加，同时 RNAPII 启动子占据保持或增加。这些基因中有相当数量的基因编码与肿瘤生长和转移相关的因子，表明转化细胞可能会迅速对 TPL/THZ 抑制剂产生耐药性。其中一些基因也对 THZ1 有反应性过表达，其耗竭增强了 TPL 的毒性，可能是新的抗癌靶点。
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