@article{449adcb61b824fa6bb2c65585b19f3e2,
title = "Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy",
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. Targeting transcriptional elongation with small-molecule inhibitors of the super elongation complex blocks transcriptional programs driven by the oncogene MYC",
keywords = "MYC, SEC, processive elongation, promoter-proximal pausing, super elongation complex, transcription elongation, transcriptional addiction in cancer",
author = "Kaiwei Liang and Smith, {Edwin R.} and Yuki Aoi and Stoltz, {Kristen L.} and Hiroaki Katagi and Woodfin, {Ashley R.} and Rendleman, {Emily J.} and Marshall, {Stacy A.} and Murray, {David C.} and Lu Wang and Ozark, {Patrick A.} and Mishra, {Rama K.} and Rintaro Hashizume and Schiltz, {Gary E.} and Ali Shilatifard",
note = "Funding Information: We thank Dr. David Bentley for the slow and fast Pol II mutant cells and Dr. Yibing Kang for the MDA231-LM2 cells. We thank Dr. Lihua Zou for help with the Hidden Markov analysis. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: J-Lat full-length clone (6.3) from Dr. Eric Verdin. A part of this work was performed by the Northwestern University ChemCore, which is funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. L.W. was supported by the Training Program in Signal Transduction and Cancer (T32CA070085). Y.A. was supported by a JSPS Research Fellowship for Young Scientists. E.R.S. was supported by the National Cancer Institute grant R50CA211428. Studies on transcription elongation control in the Shilatifard laboratory were supported by the National Cancer Institute grant R01CA214035 to A.S. Funding Information: We thank Dr. David Bentley for the slow and fast Pol II mutant cells and Dr. Yibing Kang for the MDA231-LM2 cells. We thank Dr. Lihua Zou for help with the Hidden Markov analysis. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: J-Lat full-length clone (6.3) from Dr. Eric Verdin. A part of this work was performed by the Northwestern University ChemCore, which is funded by Cancer Center Support Grant P30CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center, and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust . L.W. was supported by the Training Program in Signal Transduction and Cancer ( T32CA070085 ). Y.A. was supported by a JSPS Research Fellowship for Young Scientists . E.R.S. was supported by the National Cancer Institute grant R50CA211428 . Studies on transcription elongation control in the Shilatifard laboratory were supported by the National Cancer Institute grant R01CA214035 to A.S. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = oct,
day = "18",
doi = "10.1016/j.cell.2018.09.027",
language = "English (US)",
volume = "175",
pages = "766--779.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}
