Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells

Norihisa Uehara, Katsuhiko Yoshizawa, Airo Tsubura

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 SCF Skp2-Cks1 (Skp1/Cul1/F-box protein) ubiquitin ligase complex, in the regulation of p27 and p21 during vorinostatinduced 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. Vorinostatinduced 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.

Original languageEnglish
Pages (from-to)105-110
Number of pages6
JournalOncology reports
Volume28
Issue number1
DOIs
Publication statusPublished - Jul 1 2012
Externally publishedYes

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S-Phase Kinase-Associated Proteins
CDC2 Protein Kinase
Protein Stability
Breast Neoplasms
Proteins
F-Box Proteins
Messenger RNA
Histone Deacetylase Inhibitors
Cyclin-Dependent Kinases
Protein S
MCF-7 Cells
Bromodeoxyuridine
Cycloheximide
Ligases
Growth
Ubiquitin
S Phase
Half-Life
Down-Regulation
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells. / Uehara, Norihisa; Yoshizawa, Katsuhiko; Tsubura, Airo.

In: Oncology reports, Vol. 28, No. 1, 01.07.2012, p. 105-110.

Research output: Contribution to journalArticle

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