Abstract
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.
Highlights
Cancer cells are known to be addicted to high levels of transcription as the enhanced expression of a plethora of molecules is required for the generation and the maintenance of a transformed phenotype [1,2]
To analyse whether NT cells are more sensitive than TAM cells when TFIIH is affected, we evaluate by flow cytometry viability of NT and TAM cells which were incubated with TPL, THZ1 or both chemicals at different concentrations and for different times
We found that 94 genes upregulated by TPL that correlated with an increase in the occupancy of RNA polymerase II (RNAPII) in the oncogenesis model used here were upregulated by THZ1 in the oesophageal cancer cell line
Summary
Cancer cells are known to be addicted to high levels of transcription as the enhanced expression of a plethora of molecules is required for the generation and the maintenance of a transformed phenotype [1,2]. This information suggests that the different factors that participate in general transcriptional activation by RNA polymerase II (RNAPII) could be targets for treating cancer. The PIC includes the TFIID complex, RNAPII, TFIIB, TFIIA, TFIIF, TFIIE and TFIIH [3]. The release of paused RNAPII is conducted by the positive-elongation factor p-TEFb [6,7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
