HDAC3 functions as a positive regulator in Notch signal transduction
Francesca Ferrante, Benedetto Daniele Giaimo, Marek Bartkuhn, Tobias Zimmermann, Viola Close, Daniel Mertens, Andrea Nist, Thorsten Stiewe, Johanna Meier‐Soelch, Michael Kracht, Steffen Just, Patricia Klöble, Franz Oswald, Tilman Borggrefe
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.