DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias

Mathias Boulanger, Mays Aqrouq, Denis Tempé, Chamseddine Kifagi, Marko Ristic, Dana Akl, Rawan Hallal, Aude Carusi, Ludovic Gabellier, Marion De Toledo, Jon Otti Sigurdsson, Tony Kaoma, Charlotte Andrieu-Soler, Thierry Forné, Eric Soler, Yosr Hicheri, Elise Gueret, Laurent Vallar, Jesper V. Olsen, Guillaume CartronMarc Piechaczyk, Guillaume Bossis*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes.

Original languageEnglish
Pages (from-to)8413-8433
Number of pages21
JournalNucleic Acids Research
Volume51
Issue number16
Early online date18 Jul 2023
DOIs
Publication statusPublished - 8 Sept 2023

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