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PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers
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2019 (Engelska)Ingår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 26, nr 9, s. 1615-1630Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

PARP3 has been shown to be a key driver of TGF beta-induced epithelial-to-mesenchymal transition (EMT) and sternness in breast cancer cells, emerging as an attractive therapeutic target. Nevertheless, the therapeutic value of PARP3 inhibition has not yet been assessed. Here we investigated the impact of the absence of PARP3 or its inhibition on the tumorigenicity of BRCA1-proficient versus BRCA1-deficient breast cancer cell lines, focusing on the triple-negative breast cancer subtype (TNBC). We show that PARP3 knockdown exacerbates centrosome amplification and genome instability and reduces survival of BRCA1-deficient TNBC cells. Furthermore, we engineered PARP3(-/- )BRCA1-deficient or BRCA1-proficient TNBC cell lines using the CRISPR/nCas9(D10A) gene editing technology and demonstrate that the absence of PARP3 selectively suppresses the growth, survival and in vivo tumorigenicity of BRCA1-deficient TNBC cells, mechanistically via effects associated with an altered Rictor/mTORC2 signaling complex resulting from enhanced ubiquitination of Rictor. Accordingly, PARP3 interacts with and ADP-ribosylates GSK3 beta, a positive regulator of Rictor ubiquitination and degradation. Importantly, these phenotypes were rescued by re-expression of a wild-type PARP3 but not by a catalytic mutant, demonstrating the importance of PARP3's catalytic activity. Accordingly, reduced survival and compromised Rictor/mTORC2 signaling were also observed using a cell-permeable PARP3-specific inhibitor. We conclude that PARP3 and BRCA1 are synthetic lethal and that targeting PARP3's catalytic activity is a promising therapeutic strategy for BRCA1-associated cancers via the Rictor/mTORC2 signaling pathway.

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Nature Publishing Group, 2019. Vol. 26, nr 9, s. 1615-1630
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Biokemi och molekylärbiologi Cellbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-162838DOI: 10.1038/s41418-018-0233-1ISI: 000480648400005PubMedID: 30442946OAI: oai:DiVA.org:umu-162838DiVA, id: diva2:1351081
Tillgänglig från: 2019-09-13 Skapad: 2019-09-13 Senast uppdaterad: 2019-09-13Bibliografiskt granskad

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Elofsson, Mikael

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Tissier, AgnèsElofsson, Mikael
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Cell Death and Differentiation
Biokemi och molekylärbiologiCellbiologi

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