PARP3 supervises G9a-mediated repression of adhesion and hypoxia-responsive genes in glioblastoma cells

In breast cancer, Poly(ADP-ribose) polymerase 3 (PARP3) has been identified as a key driver of tumor aggressiveness exemplifying its selective inhibition as a promising surrogate for clinical activity onto difficult-to-treat cancers. Here we explored the role of PARP3 in the oncogenicity of glioblas...

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Bibliographic Details
Published in:Scientific reports 2022-09, Vol.12 (1), p.15534-15534, Article 15534
Main Authors: Nguekeu-Zebaze, Leonel, Hanini, Najat, Noll, Aurélia, Wadier, Nadège, Amé, Jean-Christophe, Roegel, Lisa, Dantzer, Françoise
Format: Article
Language:English
Subjects:
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631/80
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Adhesion
Biochemistry, Molecular Biology
Brain cancer
Brain tumors
Breast cancer
Cancer
Cell proliferation
Cytoskeleton
Gene silencing
Genomics
Glioblastoma
Glioblastoma cells
Histone H3
Histone methyltransferase
Humanities and Social Sciences
Hypoxia
Life Sciences
Lysine
Methyltransferase
MLH1 protein
multidisciplinary
Neurobiology
Neurons and Cognition
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
Ribose
Runx3 protein
Science
Science (multidisciplinary)
Tumors
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Summary:In breast cancer, Poly(ADP-ribose) polymerase 3 (PARP3) has been identified as a key driver of tumor aggressiveness exemplifying its selective inhibition as a promising surrogate for clinical activity onto difficult-to-treat cancers. Here we explored the role of PARP3 in the oncogenicity of glioblastoma, the most aggressive type of brain cancer. The absence of PARP3 did not alter cell proliferation nor the in vivo tumorigenic potential of glioblastoma cells. We identified a physical and functional interaction of PARP3 with the histone H3 lysine 9 methyltransferase G9a. We show that PARP3 helps to adjust G9a-dependent repression of the adhesion genes Nfasc and Parvb and the hypoxia-responsive genes Hif-2α , Runx3 , Mlh1 , Ndrg1, Ndrg2 and Ndrg4 . Specifically for Nfasc , Parvb and Ndrg4 , PARP3/G9a cooperate for an adjusted establishment of the repressive mark H3K9me2. While examining the functional consequence in cell response to hypoxia, we discovered that PARP3 acts to maintain the cytoskeletal microtubule stability. As a result, the absence of PARP3 markedly increases the sensitivity of glioblastoma cells to microtubule-destabilizing agents providing a new therapeutic avenue for PARP3 inhibition in brain cancer therapy.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-19525-6