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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,...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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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. |
format | Online Article Text |
id | pubmed-9390996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
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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