title: Vorinostat enhances protein stability of p27 and p21 through negative             regulation of Skp2 and Cks1 in human breast cancer cells.
abstract: Vorinostat is a histone deacetylase inhibitor that blocks cancer cell proliferation             through the regulation of cyclin-dependent kinase inhibitors. We, herein, examined             the involvement of S-phase kinase-associated protein 2 (Skp2) and cyclin-dependent             kinase subunit 1 (Cks1), the components of the SCFSkp2-Cks1 (Skp1/Cul1/F-box protein)             ubiquitin ligase complex, in the regulation of p27 and p21 during vorinostat-induced             growth arrest of MDA-MB-231 and MCF-7 human breast cancer cells. Vorinostat significantly             reduced BrdU incorporation in MDA-MB-231 and MCF-7 cells, which was associated             with increased p27 and p21 protein levels without concomitant induction of p27             mRNA. Vorinostat-induced accumulation of p27 and p21 proteins was inversely correlated             with the mRNA and protein levels of Skp2 and Cks1. Cycloheximide chase analysis             revealed that vorinostat increased the half-life of p27 and p21 proteins. The             accumulation of p27 and p21 proteins was attenuated by forced expression of Skp2             and Cks1, which conferred resistance to the vorinostat-induced S-phase reduction.             These results suggest that vorinostat-induced growth arrest may be in part due             to the enhanced protein stability of p27 and p21 through the downregulation of             Skp2 and Cks1.
authors.affiliation: Second Department of Pathology, Kansai Medical University, Moriguchi-shi, Osaka 570-8506, Japan. ueharan@takii.kmu.ac.jp
authors.forename: Norihisa
authors.initials: N
authors.lastname: Uehara
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Airo
authors.initials: A
authors.lastname: Tsubura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D055550:Protein Stability; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; C093090:CKS1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006877:Hydroxamic Acids; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077337:Vorinostat; D042846:CDC2-CDC28 Kinases