HDAC3 functions as a positive regulator in Notch signal transduction

Nucleic Acids Res. 2020 Apr 17;48(7):3496-3512. doi: 10.1093/nar/gkaa088.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism*
  • Humans
  • Leukemia / enzymology
  • Leukemia / metabolism*
  • Lysine / metabolism
  • Mice
  • Mutation
  • Peptides, Cyclic / pharmacology
  • Protein Stability
  • Receptor, Notch1 / chemistry
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction*


  • Histone Deacetylase Inhibitors
  • NOTCH1 protein, human
  • Notch1 protein, mouse
  • Peptides, Cyclic
  • Receptor, Notch1
  • apicidin
  • Histone Deacetylases
  • histone deacetylase 3
  • Lysine