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EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles...

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Autores principales: Durbin, Adam D., Wang, Tingjian, Wimalasena, Virangika K., Zimmerman, Mark W., Li, Deyao, Dharia, Neekesh V., Mariani, Luca, Shendy, Noha A.M., Nance, Stephanie, Patel, Anand G., Shao, Ying, Mundada, Maya, Maxham, Lily, Park, Paul M.C., Sigua, Logan H., Morita, Ken, Conway, Amy Saur, Robichaud, Amanda L., Perez-Atayde, Antonio R., Bikowitz, Melissa J., Quinn, Taylor R., Wiest, Olaf, Easton, John, Schönbrunn, Ernst, Bulyk, Martha L., Abraham, Brian J., Stegmaier, Kimberly, Look, A. Thomas, Qi, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904277/
https://www.ncbi.nlm.nih.gov/pubmed/34772733
http://dx.doi.org/10.1158/2159-8290.CD-21-0385
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author Durbin, Adam D.
Wang, Tingjian
Wimalasena, Virangika K.
Zimmerman, Mark W.
Li, Deyao
Dharia, Neekesh V.
Mariani, Luca
Shendy, Noha A.M.
Nance, Stephanie
Patel, Anand G.
Shao, Ying
Mundada, Maya
Maxham, Lily
Park, Paul M.C.
Sigua, Logan H.
Morita, Ken
Conway, Amy Saur
Robichaud, Amanda L.
Perez-Atayde, Antonio R.
Bikowitz, Melissa J.
Quinn, Taylor R.
Wiest, Olaf
Easton, John
Schönbrunn, Ernst
Bulyk, Martha L.
Abraham, Brian J.
Stegmaier, Kimberly
Look, A. Thomas
Qi, Jun
author_facet Durbin, Adam D.
Wang, Tingjian
Wimalasena, Virangika K.
Zimmerman, Mark W.
Li, Deyao
Dharia, Neekesh V.
Mariani, Luca
Shendy, Noha A.M.
Nance, Stephanie
Patel, Anand G.
Shao, Ying
Mundada, Maya
Maxham, Lily
Park, Paul M.C.
Sigua, Logan H.
Morita, Ken
Conway, Amy Saur
Robichaud, Amanda L.
Perez-Atayde, Antonio R.
Bikowitz, Melissa J.
Quinn, Taylor R.
Wiest, Olaf
Easton, John
Schönbrunn, Ernst
Bulyk, Martha L.
Abraham, Brian J.
Stegmaier, Kimberly
Look, A. Thomas
Qi, Jun
author_sort Durbin, Adam D.
collection PubMed
description Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells. SIGNIFICANCE: EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner. This article is highlighted in the In This Issue feature, p. 587
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spelling pubmed-89042772022-03-09 EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma Durbin, Adam D. Wang, Tingjian Wimalasena, Virangika K. Zimmerman, Mark W. Li, Deyao Dharia, Neekesh V. Mariani, Luca Shendy, Noha A.M. Nance, Stephanie Patel, Anand G. Shao, Ying Mundada, Maya Maxham, Lily Park, Paul M.C. Sigua, Logan H. Morita, Ken Conway, Amy Saur Robichaud, Amanda L. Perez-Atayde, Antonio R. Bikowitz, Melissa J. Quinn, Taylor R. Wiest, Olaf Easton, John Schönbrunn, Ernst Bulyk, Martha L. Abraham, Brian J. Stegmaier, Kimberly Look, A. Thomas Qi, Jun Cancer Discov Research Articles Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells. SIGNIFICANCE: EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner. This article is highlighted in the In This Issue feature, p. 587 American Association for Cancer Research 2022-03-01 2022-03-08 /pmc/articles/PMC8904277/ /pubmed/34772733 http://dx.doi.org/10.1158/2159-8290.CD-21-0385 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Research Articles
Durbin, Adam D.
Wang, Tingjian
Wimalasena, Virangika K.
Zimmerman, Mark W.
Li, Deyao
Dharia, Neekesh V.
Mariani, Luca
Shendy, Noha A.M.
Nance, Stephanie
Patel, Anand G.
Shao, Ying
Mundada, Maya
Maxham, Lily
Park, Paul M.C.
Sigua, Logan H.
Morita, Ken
Conway, Amy Saur
Robichaud, Amanda L.
Perez-Atayde, Antonio R.
Bikowitz, Melissa J.
Quinn, Taylor R.
Wiest, Olaf
Easton, John
Schönbrunn, Ernst
Bulyk, Martha L.
Abraham, Brian J.
Stegmaier, Kimberly
Look, A. Thomas
Qi, Jun
EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma
title EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma
title_full EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma
title_fullStr EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma
title_full_unstemmed EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma
title_short EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma
title_sort ep300 selectively controls the enhancer landscape of mycn-amplified neuroblastoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904277/
https://www.ncbi.nlm.nih.gov/pubmed/34772733
http://dx.doi.org/10.1158/2159-8290.CD-21-0385
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