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

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.

SUMOylation inhibitor TAK-981 (subasumstat) synergizes with 5-azacitidine in preclinical models of acute myeloid leukemia

“…Of note, we have recently shown that inhibition of SUMOylation limits the transcriptional reprogramming induced by DNR in AML cells after few hours of treatment. 50 This suggests that inhibitors of SUMOylation could have different global impacts on gene expression depending on the duration of the treatment (hours vs . days) and/or the drugs they are associated with.…”

Distinctive tumorigenic significance and innovative oncology targets of SUMOylation

“…In 2017, ML-792 was authenticated to selectively decline SAE1/2 enzyme activity and global SUMOylation level via establishing an adduct with SUMO in an ATP-dependent manner catalyzed by the enzyme itself 111 . In acute myeloid leukemia, ML-792 treatment induces the deconjugation of all the SUMO-2/3 targets and blunts Daunorubicin-mediated transcriptional reprogramming 114 . ML-93 as the derivative of ML-792 manifests a robust selectivity to hinder the SUMOylation via an identical mechanism of action in pancreatic cancer, contributing to G2/M phase arrest and apoptosis 112 .…”