Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy
Open accessAbstract
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.
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Factors regulating RNA Pol II velocity play an essential role in cells.
“Factors regulating RNA Pol II velocity therefore play an essential role in cells and are the topic of several recent studies using genome‐wide RNA Pol II speed measurement methods (Table 2) (Saponaro et al, 2014; Liang et al, 2018; Baluapuri et al, 2019; Cortazar et al, 2019; Gregersen et al, 2019; Hou et al, 2019; Sheridan et al, 2019; Fan et al, 2020).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Liang et al, 2018
MYC is required for fast transcription elongation.
“Moreover, the transcription factor MYC, which directly binds to Spt5 and recruits it to promoters, allowing Spt5 transfer onto RNA Pol II (Baluapuri et al, 2019), has been shown to be required for fast transcription elongation (Liang et al, 2018; Baluapuri et al, 2019; Caggiano et al, 2019).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Liang et al, 2018
Disruption of the super elongation complex slows down RNA Pol II.
“In addition to its role in promoter‐proximal pause release and elongation processivity, the SEC facilitates RNA Pol II transcription, as disruption of this complex slows down RNA Pol II (Liang et al, 2018).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Liang et al, 2018
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References 73 · Cited by 124
- Authors
- Liang, K., Smith, E. R., Aoi, Y., Stoltz, K. L., Katagi, H., Woodfin, A. R., Rendleman, E. J., Marshall, S. A., Murray, D. C., Wang, L., Ozark, P. A., Mishra, R. K., Hashizume, R., Schiltz, G. E., & Shilatifard, A.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Shilatifard, Ali
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 175
- Issue
- 3
- Pages
- 766-779.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6422358
- OpenAlex
- W2896104239
- Cited by
- 124
- References
- 73
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 15 · 2023: 19 · 2022: 16 · 2021: 23 · 2020: 16 · 2019: 12 · 2018: 2
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R50CA211428, R01CA214035)
- Chicago Community Trust
- Training Program in Signal Transduction and Cancer (T32CA070085)
- JSPS Research Fellowship for Young Scientists
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- super elongation complex, P-TEFb, AFF4, peptidomimetic inhibitors, promoter-proximal pausing, heat shock response, MYC-driven cancer, small molecule inhibitors, ELL2
- MeSH terms
- Animals, Antineoplastic Agents, Drosophila, Female, Humans, Male, Mice, Inbred BALB C, Neoplasms, Experimental, Protein Binding, Repressor Proteins, RNA Polymerase II, Proto-Oncogene Proteins c-myc, Heat-Shock Response, Transcriptional Elongation Factors, Positive Transcriptional Elongation Factor B, HCT116 Cells, Mice, Small Molecule Libraries, HEK293 Cells, Transcription Elongation, Genetic
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