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Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy

ABSTRACT: The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.

ORGANISM(S): Homo sapiens Drosophila melanogaster

PROVIDER: GSE112608 | GEO | 2018/10/26

REPOSITORIES: GEO

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SPT6 functions in transcriptional pause/release via PAF1C recruitment

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2022-08-09 | PXD033771 | Pride

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SPT6 functions in transcriptional pause-release via PAF1C recruitment [ChIP-seq]

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NELF regulates a promoter-proximal step distinct from RNA Pol II pause-release

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2021-07-15 | PXD024457 | Pride

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2015-12-11 | E-GEOD-62171 | biostudies-arrayexpress

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