TY - JOUR
T1 - DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
AU - Boulanger, Mathias
AU - Aqrouq, Mays
AU - Tempé, Denis
AU - Kifagi, Chamseddine
AU - Ristic, Marko
AU - Akl, Dana
AU - Hallal, Rawan
AU - Carusi, Aude
AU - Gabellier, Ludovic
AU - De Toledo, Marion
AU - Sigurdsson, Jon Otti
AU - Kaoma, Tony
AU - Andrieu-Soler, Charlotte
AU - Forné, Thierry
AU - Soler, Eric
AU - Hicheri, Yosr
AU - Gueret, Elise
AU - Vallar, Laurent
AU - Olsen, Jesper V.
AU - Cartron, Guillaume
AU - Piechaczyk, Marc
AU - Bossis, Guillaume
N1 - Funding Information:
CNRS, Ligue Nationale contre le Cancer (Equipe Labellisée to MP and PhD fellowships to M.B. and D.A.); Fondation de France [2011-00025575]; FRM [FDT20140930973 to M.R., FDM201906008566 to L.G.]; Fondation ARC (to G.B.); the HEMODIAG_2020 collection of clinical data and patient samples was funded by the Montpellier University Hospital, the Montpellier SIRIC and the Languedoc-Roussillon Region; M.G.X. acknowledges financial support from the France Génomique National infrastructure, funded as part of ‘Investissements d’Avenir’ program managed by the Agence Nationale pour la Recherche [ANR-10-INBS-09]; work at Novo Nordisk Foundation Center for Protein Research (CPR) is funded in part by a generous donation from the Novo Nordisk Foundation [NNF14CC0001]; Danish Cancer Society KBVU [R90-A5844]. Funding for open access charge: CNRS.
Publisher Copyright:
© 2023 The Author(s).
PY - 2023/9/8
Y1 - 2023/9/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85172212653&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37462077
U2 - 10.1093/nar/gkad581
DO - 10.1093/nar/gkad581
M3 - Article
C2 - 37462077
SN - 0305-1048
VL - 51
SP - 8413
EP - 8433
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 16
ER -