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.

中文翻译：

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TFIIH 活性的破坏会产生应激基因表达反应，并揭示可能的抗癌新靶点。


小分子雷公藤甲素 (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 肿瘤发生模型来比较 TFIIH 抑制剂在转化细胞及其祖细胞之间的作用。我们报告肿瘤细胞对 TPL 或 THZ1 表现出高度增加的敏感性，并且两者的组合具有协同效应。 TPL 影响 XPB 和 p52 之间的相互作用，导致 XPB、p52 和 p8 水平降低，但不影响其他 TFIIH 亚基。 RNA-Seq 和 RNAPII-ChIP-Seq 实验表明，尽管许多转录物的水平降低，但在 TPL 处理后，大量转录物的水平有所增加，且 RNAPII 启动子占据率保持或增加。这些基因中有大量编码与肿瘤生长和转移相关的因子，这表明转化细胞可能会迅速产生对 TPL/THZ 抑制剂的耐药性。其中一些基因也会因 THZ1 的反应而过度表达，THZ1 的缺失会增强 TPL 的毒性，并且可能成为抗癌的新靶标。