Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
Institute for Genetics, University of Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany.
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.
异常的 Notch 信号在 T 细胞急性淋巴细胞白血病（T-ALL）和慢性淋巴细胞白血病（CLL）中起着关键作用。Notch1 细胞内域（NICD1）的泛素依赖性蛋白酶体降解控制着 Notch 反应的幅度和持续时间，这是白血病发生过程的一个标志。在这里，我们表明 HDAC3 直接控制 NICD1 的乙酰化水平，从而直接影响 NICD1 蛋白的稳定性。HDAC3 的遗传功能丧失或纳摩尔浓度的 HDAC 抑制剂 apicidin 都会导致 Notch 靶基因的下调，同时伴随着局部组蛋白乙酰化的减少。重要的是，HDAC3 不敏感的 NICD1 突变体更稳定，但生物学活性更低。总的来说，这些数据显示了一种新的依赖于 HDAC3 和乙酰化的机制，可能被用来治疗 Notch1 依赖性白血病。
