Abstract:
:Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. Here, we show that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an HDAC3-insensitive NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1-dependent leukemias.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Ferrante F,Giaimo BD,Bartkuhn M,Zimmermann T,Close V,Mertens D,Nist A,Stiewe T,Meier-Soelch J,Kracht M,Just S,Klöble P,Oswald F,Borggrefe Tdoi
10.1093/nar/gkaa088subject
Has Abstractpub_date
2020-04-17 00:00:00pages
3496-3512issue
7eissn
0305-1048issn
1362-4962pii
5763097journal_volume
48pub_type
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