Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy.
Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy.
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DOI：
10.1016/j.cell.2018.09.027
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发表时间：
2018-10-18
期刊：
影响因子：
64.5
通讯作者：
Shilatifard A
中科院分区：
文献类型：
--
作者：
Liang K;Smith ER;Aoi Y;Stoltz KL;Katagi H;Woodfin AR;Rendleman EJ;Marshall SA;Murray DC;Wang L;Ozark PA;Mishra RK;Hashizume R;Schiltz GE;Shilatifard A
通过释放RNA聚合酶II（Pol II）及其P-TEFb模块并促进其ELL 2亚基的转录持续性，需要超延伸复合物（SEC）进行稳健和高效的转录。SEC的功能障碍导致多种人类疾病，包括癌症。在这里，我们确定拟肽先导化合物，KL-1及其结构同源物KL-2，破坏SEC支架蛋白AFF 4和PTEFB之间的相互作用，导致从启动子近端暂停位点的Pol II的释放受损和进行性转录延长的平均速率降低。SEC是诱导热休克基因所必需的，并且用KL-1和KL-2处理细胞减弱了从果蝇到人的热休克反应。SEC抑制下调哺乳动物细胞中MYC和MYC依赖性转录程序，并延迟MYC驱动癌症的小鼠异种移植模型中的肿瘤进展，表明SEC的小分子破坏物可用于MYC诱导的癌症的靶向治疗。用超延伸复合物的小分子抑制剂靶向转录延伸阻断由癌基因MYC驱动的转录程序
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 PTEFb, 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. Targeting transcriptional elongation with a small molecule inhibitor of the Super Elongation Complex blocks transcriptional programs driven by the oncogene MYC
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影响因子：
16
作者：
He N;Liu M;Hsu J;Xue Y;Chou S;Burlingame A;Krogan NJ;Alber T;Zhou Q
通讯作者：
Zhou Q
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Erb MA;Scott TG;Li BE;Xie H;Paulk J;Seo HS;Souza A;Roberts JM;Dastjerdi S;Buckley DL;Sanjana NE;Shalem O;Nabet B;Zeid R;Offei-Addo NK;Dhe-Paganon S;Zhang F;Orkin SH;Winter GE;Bradner JE
通讯作者：
Bradner JE
影响因子：
64.5
作者：
Ji X;Zhou Y;Pandit S;Huang J;Li H;Lin CY;Xiao R;Burge CB;Fu XD
通讯作者：
Fu XD
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS