例如:"lncRNA", "apoptosis", "WRKY"

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

Cell. 2018 Oct 18;175(3):766-779.e17
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 8
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 8
+ et al

[No authors listed]

Author information
  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 5 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.
  • 6 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.
  • 7 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.
  • 8 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. Electronic address: ash@northwestern.edu.

摘要


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.

KEYWORDS: MYC, SEC, processive elongation, promoter-proximal pausing, super elongation complex, transcription elongation, transcriptional addiction in cancer