| Literature DB >> 33768209 |
Isabelle Roeschert1, Evon Poon2, Anton G Henssen3, Heathcliff Dorado Garcia3, Marco Gatti4, Celeste Giansanti5, Yann Jamin6, Carsten P Ade1, Peter Gallant1, Christina Schülein-Völk7, Petra Beli8, Mark Richards9, Mathias Rosenfeldt10, Matthias Altmeyer4, John Anderson11, Angelika Eggert3, Matthias Dobbelstein5, Richard Bayliss9, Louis Chesler2, Gabriele Büchel1,12, Martin Eilers1.
Abstract
Amplification of MYCN is the driving oncogene in a subset of high-risk neuroblastoma. The MYCN protein and the Aurora-A kinase form a complex during S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription-replication conflicts and activates the Ataxia telangiectasia and Rad3 related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription-replication conflicts is an effective therapy for MYCN-driven neuroblastoma (141 words).Entities:
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Year: 2021 PMID： 33768209 PMCID： PMC7610389 DOI： 10.1038/s43018-020-00171-8
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347