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RB1 loss triggers dependence on ESRRG in retinoblastoma

Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes,...

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Autores principales: Field, Matthew G., Kuznetsoff, Jeffim N., Zhang, Michelle G., Dollar, James J., Durante, Michael A., Sayegh, Yoseph, Decatur, Christina L., Kurtenbach, Stefan, Pelaez, Daniel, Harbour, J. William
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9390996/
https://www.ncbi.nlm.nih.gov/pubmed/35984874
http://dx.doi.org/10.1126/sciadv.abm8466
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author Field, Matthew G.
Kuznetsoff, Jeffim N.
Zhang, Michelle G.
Dollar, James J.
Durante, Michael A.
Sayegh, Yoseph
Decatur, Christina L.
Kurtenbach, Stefan
Pelaez, Daniel
Harbour, J. William
author_facet Field, Matthew G.
Kuznetsoff, Jeffim N.
Zhang, Michelle G.
Dollar, James J.
Durante, Michael A.
Sayegh, Yoseph
Decatur, Christina L.
Kurtenbach, Stefan
Pelaez, Daniel
Harbour, J. William
author_sort Field, Matthew G.
collection PubMed
description Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify previously unknown Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death, which is exacerbated in hypoxia. These findings reveal a previously unidentified dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.
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spelling pubmed-93909962022-08-26 RB1 loss triggers dependence on ESRRG in retinoblastoma Field, Matthew G. Kuznetsoff, Jeffim N. Zhang, Michelle G. Dollar, James J. Durante, Michael A. Sayegh, Yoseph Decatur, Christina L. Kurtenbach, Stefan Pelaez, Daniel Harbour, J. William Sci Adv Biomedicine and Life Sciences Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify previously unknown Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death, which is exacerbated in hypoxia. These findings reveal a previously unidentified dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb. American Association for the Advancement of Science 2022-08-19 /pmc/articles/PMC9390996/ /pubmed/35984874 http://dx.doi.org/10.1126/sciadv.abm8466 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Field, Matthew G.
Kuznetsoff, Jeffim N.
Zhang, Michelle G.
Dollar, James J.
Durante, Michael A.
Sayegh, Yoseph
Decatur, Christina L.
Kurtenbach, Stefan
Pelaez, Daniel
Harbour, J. William
RB1 loss triggers dependence on ESRRG in retinoblastoma
title RB1 loss triggers dependence on ESRRG in retinoblastoma
title_full RB1 loss triggers dependence on ESRRG in retinoblastoma
title_fullStr RB1 loss triggers dependence on ESRRG in retinoblastoma
title_full_unstemmed RB1 loss triggers dependence on ESRRG in retinoblastoma
title_short RB1 loss triggers dependence on ESRRG in retinoblastoma
title_sort rb1 loss triggers dependence on esrrg in retinoblastoma
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9390996/
https://www.ncbi.nlm.nih.gov/pubmed/35984874
http://dx.doi.org/10.1126/sciadv.abm8466
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