title: CDK4-CDK6 inhibitors induce autophagy-mediated degradation of DNMT1 and facilitate the senescence antitumor response.
abstract: Senescence is a natural anticancer defense program disabled in tumor cells. We discovered that deregulated CDK4 (cyclin dependant kinase 4) and CDK6 activities contribute to senescence bypass during tumorigenesis and that their inhibition restores the senescence response in tumor cells. CDK4 and CDK6 phosphorylate RB1/RB, preventing its inhibitory interaction with the E2Fs, the cell cycle transcription factors. However, we also found that CDK4 interacts and phosphorylates the DNMT1 (DNA methyltransferase 1) protein protecting it from macroautophagy/autophagy-mediated protein degradation. This discovery highlights a new epigenetic component of CDK4-CDK6 signaling that could be exploited in cancer treatment.
authors.affiliation: a Department of Biochemistry and Molecular Medicine , Université de Montréal , Montréal , Québec , Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourdeau
authors.affiliation: a Department of Biochemistry and Molecular Medicine , Université de Montréal , Montréal , Québec , Canada.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D001343:Autophagy / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D002986:Clinical Trials as Topic; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: CDK4; DNMT1; PML; autophagy; cancer; epigenetic; senescence