Pericentromeric Satellite III transcripts induce etoposide resistance.
Animals
Antineoplastic Agents
/ pharmacology
Cell Cycle Proteins
/ antagonists & inhibitors
Centromere
/ genetics
DNA Methylation
/ physiology
DNA Topoisomerases, Type II
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Etoposide
/ therapeutic use
Gene Expression Regulation, Neoplastic
/ drug effects
HEK293 Cells
HeLa Cells
Humans
Male
Mice, Inbred NOD
Mice, SCID
Poly-ADP-Ribose Binding Proteins
/ drug effects
RNA, Long Noncoding
/ genetics
Transcription Factors
/ antagonists & inhibitors
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
24 05 2021
24 05 2021
Historique:
received:
17
10
2020
accepted:
10
05
2021
revised:
04
03
2021
entrez:
25
5
2021
pubmed:
26
5
2021
medline:
23
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34031359
doi: 10.1038/s41419-021-03810-9
pii: 10.1038/s41419-021-03810-9
pmc: PMC8144429
doi:
Substances chimiques
Antineoplastic Agents
0
BRD4 protein, human
0
Cell Cycle Proteins
0
Poly-ADP-Ribose Binding Proteins
0
RNA, Long Noncoding
0
Transcription Factors
0
Etoposide
6PLQ3CP4P3
DNA Topoisomerases, Type II
EC 5.99.1.3
TOP2A protein, human
EC 5.99.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
530Subventions
Organisme : University of Cologne | Center for Molecular Medicine Cologne, University of Cologne (CMMC, UoC)
ID : CMMC-A10
Organisme : University of Cologne | Center for Molecular Medicine Cologne, University of Cologne (CMMC, UoC)
ID : CMMC-A10
Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ID : SMOOSE
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : ERC CoG "EPICODE" Grant Nr. 723863
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