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

Kaiwei Liang; Edwin R Smith; Yuki Aoi; Kristen L Stoltz; Hiroaki Katagi; Ashley R Woodfin; Emily J Rendleman; Stacy A Marshall; David C Murray; Lu Wang; Patrick A Ozark; Rama K Mishra; Rintaro Hashizume; Gary E Schiltz; Ali Shilatifard

doi:10.1016/j.cell.2018.09.027

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.

Authors

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: ash@northwestern.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Drosophila
Female
HCT116 Cells
HEK293 Cells
Heat-Shock Response
Humans
Male
Mice
Mice, Inbred BALB C
Neoplasms, Experimental / drug therapy*
Positive Transcriptional Elongation Factor B / metabolism*
Protein Binding / drug effects
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA Polymerase II / metabolism
Repressor Proteins / metabolism*
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
Transcription Elongation, Genetic / drug effects*
Transcriptional Elongation Factors / metabolism*

Substances

AFF4 protein, human
Antineoplastic Agents
Proto-Oncogene Proteins c-myc
Repressor Proteins
Small Molecule Libraries
Transcriptional Elongation Factors
Positive Transcriptional Elongation Factor B
RNA Polymerase II

Abstract

Publication types

MeSH terms

Substances

Grants and funding