Cargando…
Pericentromeric Satellite III transcripts induce etoposide resistance
Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144429/ https://www.ncbi.nlm.nih.gov/pubmed/34031359 http://dx.doi.org/10.1038/s41419-021-03810-9 |
_version_ | 1783696955203911680 |
---|---|
author | Kanne, Julian Hussong, Michelle Isensee, Jörg Muñoz-López, Álvaro Wolffgramm, Jan Heß, Felix Grimm, Christina Bessonov, Sergey Meder, Lydia Wang, Jie Reinhardt, H. Christian Odenthal, Margarete Hucho, Tim Büttner, Reinhard Summerer, Daniel Schweiger, Michal R. |
author_facet | Kanne, Julian Hussong, Michelle Isensee, Jörg Muñoz-López, Álvaro Wolffgramm, Jan Heß, Felix Grimm, Christina Bessonov, Sergey Meder, Lydia Wang, Jie Reinhardt, H. Christian Odenthal, Margarete Hucho, Tim Büttner, Reinhard Summerer, Daniel Schweiger, Michal R. |
author_sort | Kanne, Julian |
collection | PubMed |
description | Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity. |
format | Online Article Text |
id | pubmed-8144429 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81444292021-06-07 Pericentromeric Satellite III transcripts induce etoposide resistance Kanne, Julian Hussong, Michelle Isensee, Jörg Muñoz-López, Álvaro Wolffgramm, Jan Heß, Felix Grimm, Christina Bessonov, Sergey Meder, Lydia Wang, Jie Reinhardt, H. Christian Odenthal, Margarete Hucho, Tim Büttner, Reinhard Summerer, Daniel Schweiger, Michal R. Cell Death Dis Article Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity. Nature Publishing Group UK 2021-05-24 /pmc/articles/PMC8144429/ /pubmed/34031359 http://dx.doi.org/10.1038/s41419-021-03810-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kanne, Julian Hussong, Michelle Isensee, Jörg Muñoz-López, Álvaro Wolffgramm, Jan Heß, Felix Grimm, Christina Bessonov, Sergey Meder, Lydia Wang, Jie Reinhardt, H. Christian Odenthal, Margarete Hucho, Tim Büttner, Reinhard Summerer, Daniel Schweiger, Michal R. Pericentromeric Satellite III transcripts induce etoposide resistance |
title | Pericentromeric Satellite III transcripts induce etoposide resistance |
title_full | Pericentromeric Satellite III transcripts induce etoposide resistance |
title_fullStr | Pericentromeric Satellite III transcripts induce etoposide resistance |
title_full_unstemmed | Pericentromeric Satellite III transcripts induce etoposide resistance |
title_short | Pericentromeric Satellite III transcripts induce etoposide resistance |
title_sort | pericentromeric satellite iii transcripts induce etoposide resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144429/ https://www.ncbi.nlm.nih.gov/pubmed/34031359 http://dx.doi.org/10.1038/s41419-021-03810-9 |
work_keys_str_mv | AT kannejulian pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT hussongmichelle pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT isenseejorg pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT munozlopezalvaro pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT wolffgrammjan pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT heßfelix pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT grimmchristina pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT bessonovsergey pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT mederlydia pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT wangjie pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT reinhardthchristian pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT odenthalmargarete pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT huchotim pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT buttnerreinhard pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT summererdaniel pericentromericsatelliteiiitranscriptsinduceetoposideresistance AT schweigermichalr pericentromericsatelliteiiitranscriptsinduceetoposideresistance |