Dynamic Methylation of Numb by Set8 Regulates Its Binding to p53 and Apoptosis
Menée sur des lignées cellulaires de cancer du sein, cette étude met en évidence un mécanisme par lequel la méthylation du gène Numb par Set8, une lysine méthyltransférase, régule sa liaison avec le gène suppresseur de tumeur p53 et favorise l'apoptose
Although Numb exhibits its tumor-suppressive function in breast cancer in part by binding to and stabilizing p53, it is unknown how the Numb-p53 interaction is regulated in cells. We found that Numb is methylated in its phosphotyrosine-binding (PTB) domain by the lysine methyltransferase Set8. Moreover, methylation uncouples Numb from p53, resulting in increased p53 ubiquitination and degradation. While Numb promotes apoptosis in a p53-dependent manner, the apoptotic function is abolished when Numb is methylated by Set8 or the Lys methylation sites in Numb are mutated. Conversely, the Numb-p53 interaction and Numb-mediated apoptosis are significantly enhanced by depletion of Set8 from cancer cells or by treating the cells with doxorubicin, a chemotherapeutic drug that causes a reduction in the mRNA and protein levels of Set8. Our work identifies the Set8-Numb-p53 signaling axis as an important regulatory pathway for apoptosis and suggests a therapeutic strategy by targeting Numb methylation. "Numb binds to p53 in the nucleus and promotes apoptosis "Numb is methylated by Set8 in the PTB domain "Lys methylation of Numb abolishes its binding to and protection of p53 "Doxorubicin induces apoptosis by promoting Numb demethylation
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