title: Histone Deacetylase Inhibitors Increase p27(Kip1) by Affecting Its Ubiquitin-Dependent Degradation through Skp2 Downregulation.
abstract: Histone deacetylase inhibitors (HDACIs) represent an intriguing class of pharmacologically active compounds. Currently, some HDACIs are FDA approved for cancer therapy and many others are in clinical trials, showing important clinical activities at well tolerated doses. HDACIs also interfere with the aging process and are involved in the control of inflammation and oxidative stress. In vitro, HDACIs induce different cellular responses including growth arrest, differentiation, and apoptosis. Here, we evaluated the effects of HDACIs on p27(Kip1), a key cyclin-dependent kinase inhibitor (CKI). We observed that HDACI-dependent antiproliferative activity is associated with p27(Kip1) accumulation due to a reduced protein degradation. p27(Kip1) removal requires a preliminary ubiquitination step due to the Skp2-SCF E3 ligase complex. We demonstrated that HDACIs increase p27(Kip1) stability through downregulation of Skp2 protein levels. Skp2 decline is only partially due to a reduced Skp2 gene expression. Conversely, the protein decrease is more profound and enduring compared to the changes of Skp2 transcript. This argues for HDACIs effects on Skp2 protein posttranslational modifications and/or on its removal. In summary, we demonstrate that HDACIs increase p27(Kip1) by hampering its nuclear ubiquitination/degradation. The findings might be of relevance in the phenotypic effects of these compounds, including their anticancer and aging-modulating activities.
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Borriello
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Naviglio
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Bencivenga
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Caldarelli
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Annunziata
authors.initials: A
authors.lastname: Tramontano
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Speranza
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Stampone
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Sapio
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi di Firenze, 50134 Firenze, Italy.
authors.forename: Aide
authors.initials: A
authors.lastname: Negri
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Oliva
authors.affiliation: Dipartimento di Scienze Cardiotoraciche e Respiratorie, Seconda Università di Napoli, 80131 Napoli, Italy.
authors.forename: Antonio Agostino
authors.initials: AA
authors.lastname: Sinisi
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Spina
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Della Ragione
mesh_terms: D018938:Caco-2 Cells; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C436291:CDKN1B protein, human; D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27