Format

Send to

Choose Destination
Nucleic Acids Res. 2020 Feb 28. pii: gkaa088. doi: 10.1093/nar/gkaa088. [Epub ahead of print]

HDAC3 functions as a positive regulator in Notch signal transduction.

Author information

1
Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
2
Institute for Genetics, University of Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany.
3
Bioinformatics and Systems Biology, University of Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany.
4
University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine III, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
5
Cooperation Unit "Mechanisms of Leukemogenesis" (B061), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg Germany.
6
Genomics Core Facility, Institute of Molecular Oncology, Philipps-University, Hans-Meerwein-Str. 3, 35043 Marburg, Germany.
7
Rudolf Buchheim Institute of Pharmacology, University of Giessen, Schubertstrasse 81, 35392 Giessen, Germany.
8
University Medical Center Ulm, Center for Internal Medicine, Molecular Cardiology, Department of Internal Medicine II, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
9
University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, Albert-Einstein-Allee 23, 89081 Ulm, Germany.

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.

PMID:
32107550
DOI:
10.1093/nar/gkaa088

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center