Histone Deacetylase Inhibitors Increase P27(Kip1) by Affecting Its Ubiquitin-Dependent Degradation Through Skp2 Downregulation

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2015 Dec 19

PMID 26682002

Citations 8

Authors

Adriana Borriello

Silvio Naviglio

Debora Bencivenga

Ilaria Caldarelli

Annunziata Tramontano

Maria Carmela Speranza

Emanuela Stampone

Luigi Sapio

Aide Negri

Adriana Oliva

Antonio Agostino Sinisi

Annamaria Spina

Fulvio Della Ragione

Affiliations

Soon will be listed here.

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.

Citing Articles

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