Histone deacetylase inhibitor, Trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells

Title: Histone deacetylase inhibitor, Trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells
Author(s): Alao, JP
Stavropoulou, AV
Lam, EW-F
Coombes, RC
Vigushin, DM
Item Type: Journal Article
Abstract: Background Cyclin D1 is an important regulator of G1-S phase cell cycle transition and has been shown to be important for breast cancer development. GSK3β phosphorylates cyclin D1 on Thr-286, resulting in enhanced ubiquitylation, nuclear export and degradation of the cyclin in the cytoplasm. Recent findings suggest that the development of small-molecule cyclin D1 ablative agents is of clinical relevance. We have previously shown that the histone deacetylase inhibitor trichostatin A (TSA) induces the rapid ubiquitin-dependent degradation of cyclin D1 in MCF-7 breast cancer cells prior to repression of cyclin D1 gene (CCND1) transcription. TSA treatment also resulted in accumulation of polyubiquitylated GFP-cyclin D1 species and reduced levels of the recombinant protein within the nucleus. Results Here we provide further evidence for TSA-induced ubiquitin-dependent degradation of cyclin D1 and demonstrate that GSK3β-mediated nuclear export facilitates this activity. Our observations suggest that TSA treatment results in enhanced cyclin D1 degradation via the GSK3β/CRM1-dependent nuclear export/26S proteasomal degradation pathway in MCF-7 cells. Conclusion We have demonstrated that rapid TSA-induced cyclin D1 degradation in MCF-7 cells requires GSK3β-mediated Thr-286 phosphorylation and the ubiquitin-dependent 26S proteasome pathway. Drug induced cyclin D1 repression contributes to the inhibition of breast cancer cell proliferation and can sensitize cells to CDK and Akt inhibitors. In addition, anti-cyclin D1 therapy may be highly specific for treating human breast cancer. The development of potent and effective cyclin D1 ablative agents is therefore of clinical relevance. Our findings suggest that HDAC inhibitors may have therapeutic potential as small-molecule cyclin D1 ablative agents.
Publication Date: 20-Feb-2006
Date of Acceptance: 20-Feb-2006
URI: http://hdl.handle.net/10044/1/39177
DOI: http://dx.doi.org/10.1186/1476-4598-5-8
ISSN: 1476-4598
Publisher: BioMed Central
Journal / Book Title: Molecular Cancer
Volume: 5
Copyright Statement: © Alao et al. 2006. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
BIOCHEMISTRY & MOLECULAR BIOLOGY
ONCOLOGY
CELLULAR-TRANSFORMATION
PROTEASOMAL DEGRADATION
NUCLEAR EXPORT
PHOSPHORYLATION
LOCALIZATION
KINASE
OVEREXPRESSION
TRANSCRIPTION
PROTEOLYSIS
PROGRESSION
Acetylcysteine
Breast Neoplasms
Cell Line, Tumor
Cell Nucleus
Cyclin D1
Cytoplasm
Enzyme Inhibitors
Fatty Acids, Unsaturated
Female
Glycogen Synthase Kinase 3
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids
Karyopherins
Leupeptins
Proteasome Endopeptidase Complex
Proteasome Inhibitors
RNA Interference
Receptors, Cytoplasmic and Nuclear
Recombinant Fusion Proteins
Transfection
Ubiquitin
Cell Line, Tumor
Cell Nucleus
Cytoplasm
Humans
Breast Neoplasms
Hydroxamic Acids
Proteasome Endopeptidase Complex
Glycogen Synthase Kinase 3
Fatty Acids, Unsaturated
Cyclin D1
Acetylcysteine
Leupeptins
Karyopherins
Receptors, Cytoplasmic and Nuclear
Recombinant Fusion Proteins
Ubiquitin
Enzyme Inhibitors
Transfection
RNA Interference
Female
Histone Deacetylase Inhibitors
Proteasome Inhibitors
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status: Published
Article Number: 8
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



Items in Spiral are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commons