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

被引:66
作者
Alao, John P. [1 ]
Stavropoulou, Alexandra V. [1 ]
Lam, Eric W-F [1 ]
Coombes, R. Charles [1 ]
Vigushin, David M. [1 ]
机构
[1] Hammersmith Hosp, Imperial Coll, Dept Canc Med, Canc Cell Biol Sect, London W12 0NN, England
关键词
D O I
10.1186/1476-4598-5-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Cyclin D1 is an important regulator of GI-S phase cell cycle transition and has been shown to be important for breast cancer development. GSK3 beta 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 (CCNDI) 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 GSK3 beta-mediated nuclear export facilitates this activity. Our observations suggest that TSA treatment results in enhanced cyclin D1 degradation via the GSK3 beta/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 GSK3 beta-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.
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页数:11
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