4.7 Article

Pericentromeric Satellite III transcripts induce etoposide resistance

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CELL DEATH & DISEASE
卷 12, 期 6, 页码 -

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SPRINGERNATURE
DOI: 10.1038/s41419-021-03810-9

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资金

  1. Volkswagenstiftung (Lichtenberg Professorship)
  2. Deutsche Forschungsgemeinschaft [KFO-286-RP8, KFO-286-RP2, SFB-1399-B03, A01/C02]
  3. Center for Molecular Medicine Cologne [CMMC-A10]
  4. German-Israeli Foundation for Research and Development [I-65-412.202016]
  5. Else Kroner-Fresenius Stiftung [EKFS-2014-A06, 2016_Kolleg.19]
  6. Deutsche Krebshilfe [1117240, 70113041]
  7. Federal German Ministry of Science and Education (BMBF) [e:Med 01ZX1303A]
  8. North Rhine-Westfalia Ministry of Innovation and Sciences (PerMed network)
  9. European Research Concil (ERC CoG EPICODE) [723863]
  10. Projekt DEAL
  11. European Research Council (ERC) [723863] Funding Source: European Research Council (ERC)

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Non-coding RNA from pericentromeric satellite repeats, specifically SatIII, plays a crucial role in lung cancer drug resistance, possibly through mechanisms related to genome stability, cancer therapy, and endogenous stress response processes.
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.

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