HDAC3 functions as a positive regulator in Notch signal transduction.

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 Res

journal_title

Nucleic acids research

authors

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 T

doi

10.1093/nar/gkaa088

subject

Has Abstract

pub_date

2020-04-17 00:00:00

pages

3496-3512

issue

7

eissn

0305-1048

issn

1362-4962

pii

5763097

journal_volume

48

pub_type

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