Journal article

Publication year: 2020

Pages: 3496-3512

Journal: Nucleic Acids Research

Volume number: 48

Issue number: 7

ISSN: 0305-1048

eISSN: 1362-4962

Open access status: Gold

DOI Link: https://doi.org/10.1093/nar/gkaa088

Publisher: Oxford University Press

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.

Harvard Citation style: Ferrante, F., Giaimo, B., Bartkuhn, M., Zimmermann, T., Close, V., Mertens, D., et al. (2020) HDAC3 functions as a positive regulator in Notch signal transduction, Nucleic Acids Research, 48(7), pp. 3496-3512. https://doi.org/10.1093/nar/gkaa088

APA Citation style: Ferrante, F., Giaimo, B., 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. (2020). HDAC3 functions as a positive regulator in Notch signal transduction. Nucleic Acids Research. 48(7), 3496-3512. https://doi.org/10.1093/nar/gkaa088