Abstract
Post-translational modifications of Notch3 and their functional role with respect to Notch3 overexpression in T-cell leukemia are still poorly understood. We identify here a specific novel property of Notch3 that is acetylated and deacetylated at lysines 1692 and 1731 by p300 and HDAC1, respectively, a balance impaired by HDAC inhibitors (HDACi) that favor hyperacetylation. By using HDACi and a non-acetylatable Notch3 mutant carrying K/R1692−1731 mutations in the intracellular domain, we show that Notch3 acetylation primes ubiquitination and proteasomal-mediated degradation of the protein. As a consequence, Notch3 protein expression and its transcriptional activity are decreased both in vitro and in vivo in Notch3 transgenic (tg) mice, thus impairing downstream signaling upon target genes. Consistently, Notch3-induced T-cell proliferation is inhibited by HDACi, whereas it is enhanced by the non-acetylatable Notch3-K/R1692−1731 mutant. Finally, HDACi-induced Notch3 hyperacetylation prevents in vivo growth of T-cell leukemia/lymphoma in Notch3 tg mice. Together, our findings suggest a novel level of Notch signaling control in which Notch3 acetylation/deacetylation process represents a key regulatory switch, thus representing a suitable druggable target for Notch3-sustained T-cell acute lymphoblastic leukemia therapy.
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Acknowledgements
We are grateful to Dr Sonia Coni for experimental support. This work was supported by the Italian Association for Cancer Research (AIRC), the Italian Ministry of University and Research (MIUR), PRIN and FIRB Programs, the Italian Ministry of Health, the European Union (NotchIT ITN Project; FP7-MC-ITN 215761), Eleonora Lorillard Spencer Cenci Foundation and the Fondazione Roma (fellowship to RP).
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Palermo, R., Checquolo, S., Giovenco, A. et al. Acetylation controls Notch3 stability and function in T-cell leukemia. Oncogene 31, 3807–3817 (2012). https://doi.org/10.1038/onc.2011.533
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DOI: https://doi.org/10.1038/onc.2011.533
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