Co-inhibition of BET proteins and PI3Kα triggers mitochondrial apoptosis in rhabdomyosarcoma cells

Cathinka Boedicker, Michelle Hussong, Christina Grimm, Nadezda Dolgikh, Michael T Meister, Julius C Enßle, Marek Wanior, Stefan Knapp, Michal R Schweiger, Simone Fulda

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Remodeling transcription by targeting bromodomain and extraterminal (BET) proteins has emerged as promising anticancer strategy. Here, we identify a novel synergistic interaction of the BET inhibitor JQ1 with the PI3Kα-specific inhibitor BYL719 to trigger mitochondrial apoptosis and to suppress tumor growth in models of rhabdomyosarcoma (RMS). RNA-Seq revealed that JQ1/BYL719 co-treatment shifts the overall balance of BCL-2 family gene expression towards apoptosis and upregulates expression of BMF, BCL2L11 (BIM), and PMAIP1 (NOXA) while downregulating BCL2L1 (BCL-xL). These changes were confirmed by qRT-PCR and western blot analysis. Ingenuity pathway analysis (IPA) of RNA-Seq data followed by validation qRT-PCR and western blot identified MYC and FOXO3a as potential transcription factors (TFs) upstream of the observed gene expression pattern. Immunoprecipitation (IP) studies showed that JQ1/BYL719-stimulated increase in BIM expression enhances the neutralization of antiapoptotic BCL-2, BCL-xL, and MCL-1. This promotes the activation of BAK and BAX and caspase-dependent apoptosis, as (1) individual silencing of BMF, BIM, NOXA, BAK, or BAX, (2) overexpression of BCL-2 or MCL-1 or (3) the caspase inhibitor N-Benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethylketone (zVAD.fmk) all rescue JQ1/BYL719-induced cell death. In conclusion, co-inhibition of BET proteins and PI3Kα cooperatively induces mitochondrial apoptosis by proapoptotic re-balancing of BCL-2 family proteins. This discovery opens exciting perspectives for therapeutic exploitation of BET inhibitors in RMS.

Original languageEnglish
Pages (from-to)3837-3852
Number of pages16
JournalOncogene
Volume39
Issue number19
DOIs
Publication statusPublished - May 2020
Externally publishedYes

Keywords

  • Adaptor Proteins, Signal Transducing/genetics
  • Animals
  • Apoptosis/drug effects
  • Azepines/pharmacology
  • Bcl-2-Like Protein 11/genetics
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic/genetics
  • Histone Deacetylase Inhibitors/pharmacology
  • Humans
  • Mice
  • Mitochondria/drug effects
  • Myeloid Cell Leukemia Sequence 1 Protein/genetics
  • Proto-Oncogene Proteins c-bcl-2/genetics
  • RNA-Seq
  • Rhabdomyosarcoma/drug therapy
  • Thiazoles/pharmacology
  • Transcription Factors/antagonists & inhibitors
  • Triazoles/pharmacology
  • bcl-X Protein/genetics

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