title: A CDK4/6-Dependent Epigenetic Mechanism Protects Cancer Cells from PML-induced Senescence.
abstract: Promyelocytic leukemia (PML) plays a tumor suppressive role by inducing cellular senescence in response to oncogenic stress. However, tumor cell lines fail to engage in complete senescence upon PML activation. In this study, we investigated the mechanisms underlying resistance to PML-induced senescence. Here, we report that activation of the cyclin-dependent kinases CDK4 and CDK6 are essential and sufficient to impair senescence induced by PML expression. Disrupting CDK function by RNA interference or pharmacological inhibition restored senescence in tumor cells and diminished their tumorigenic potential in mouse xenograft models. Complete senescence correlated with an increase in autophagy, repression of E2F target genes, and an gene expression signature of blocked DNA methylation. Accordingly, treatment of tumor cells with inhibitors of DNA methylation reversed resistance to PML-induced senescence. Further, CDK inhibition with palbociclib promoted autophagy-dependent degradation of the DNA methyltransferase DNMT1. Lastly, we found that CDK4 interacted with and phosphorylated DNMT1 in vitro, suggesting that CDK activity is required for its stabilization. Taken together, our findings highlight a potentially valuable feature of CDK4/6 inhibitors as epigenetic modulators to facilitate activation of senescence programs in tumor cells. Cancer Res; 76(11); 3252-64. ©2016 AACR.
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Mariana
authors.initials: M
authors.lastname: Acevedo
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vernier
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Lian
authors.initials: L
authors.lastname: Mignacca
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lessard
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Huot
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada. veronique.bourdeau@umontreal.ca g.ferbeyre@umontreal.ca.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourdeau
authors.affiliation: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada. veronique.bourdeau@umontreal.ca g.ferbeyre@umontreal.ca.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; C070576:PML protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6