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.


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*


  • 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