Universität zu Köln

Boedicker, Cathinka, Hussong, Michelle, Grimm, Christina, Dolgikh, Nadezda, Meister, Michael T., Enssle, Julius C., Wanior, Marek, Knapp, Stefan, Schweiger, Michal R. and Fulda, Simone ORCID: 0000-0002-0459-6417 (2020). Co-inhibition of BET proteins and PI3K alpha triggers mitochondrial apoptosis in rhabdomyosarcoma cells. Oncogene, 39 (19). S. 3837 - 3853. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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 PI3K alpha-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-x(L)). 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-x(L), 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 PI3K alpha 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Boedicker, Cathinka UNSPECIFIED UNSPECIFIED UNSPECIFIED Hussong, Michelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Grimm, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dolgikh, Nadezda UNSPECIFIED UNSPECIFIED UNSPECIFIED Meister, Michael T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Enssle, Julius C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wanior, Marek UNSPECIFIED UNSPECIFIED UNSPECIFIED Knapp, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fulda, Simone UNSPECIFIED orcid.org/0000-0002-0459-6417 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-335663
DOI:	10.1038/s41388-020-1229-0
Journal or Publication Title:	Oncogene
Volume:	39
Number:	19
Page Range:	S. 3837 - 3853
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEMATOLOGICAL MALIGNANCIES; BROMODOMAIN INHIBITORS; SYNTHETIC LETHALITY; GENE-EXPRESSION; IDENTIFICATION; HEDGEHOG; PATHWAY; RESISTANCE; KINASE; ACTIVATION Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33566