2. Academic Validation
  3. Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy

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

  • Cell. 2018 Oct 18;175(3):766-779.e17. 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 8
Affiliations

Affiliations

  • 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: [email protected].
PMID: 30340042 DOI: 10.1016/j.cell.2018.09.027
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.

Keywords

MYC; SEC; processive elongation; promoter-proximal pausing; super elongation complex; transcription elongation; transcriptional addiction in cancer.

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