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

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Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy.
Cell ( IF 45.5 ) Pub Date : 2018-Oct-18 , DOI: 10.1016/j.cell.2018.09.027
Kaiwei Liang ₁ , Edwin R Smith ₂ , Yuki Aoi ₁ , Kristen L Stoltz ₃ , Hiroaki Katagi ₄ , Ashley R Woodfin ₁ , Emily J Rendleman ₁ , Stacy A Marshall ₁ , David C Murray ₁ , Lu Wang ₁ , Patrick A Ozark ₁ , Rama K Mishra ₅ , Rintaro Hashizume ₆ , Gary E Schiltz ₇ , Ali Shilatifard ₂

Affiliation

Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg, School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.
Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA.
Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg, School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.
Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg, School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.

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.

中文翻译：

通过 MYC 诱导的癌症治疗的 SEC 中断靶向进行性转录延伸。

超延伸复合物 (SEC) 是通过释放 RNA 聚合酶 II (Pol II) 及其 P-TEFb 模块并通过其 ELL2 亚基促进转录持续进行性而实现稳健和高效转录所必需的。SEC 的故障会导致包括癌症在内的多种人类疾病。在这里，我们确定了拟肽先导化合物 KL-1 及其结构同系物 KL-2，它们破坏了 SEC 支架蛋白 AFF4 和 P-TEFb 之间的相互作用，导致 Pol II 从启动子近端暂停位点的释放受损并减少进行性转录延伸的平均速率。SEC 是诱导热休克基因所必需的，用 KL-1 和 KL-2 处理细胞可减弱果蝇对人类的热休克反应。

更新日期：2018-10-19

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