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Critical Reviews™ in Eukaryotic Gene Expression
Impact-faktor: 1.841 5-jähriger Impact-Faktor: 1.927 SJR: 0.649 SNIP: 0.516 CiteScore™: 1.96

ISSN Druckformat: 1045-4403
ISSN Online: 2162-6502

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukarGeneExpr.v22.i3.80
pages 249-258

Tumor Suppressor Maspin as a Rheostat in HDAC Regulation to Achieve the Fine-Tuning of Epithelial Homeostasis

Alexander Kaplun
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, Detroit, MI 48201
Sijana Dzinic
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, Detroit, MI 48201
M. Margarida Bernardo
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, Detroit, MI 48201
Shijie Sheng
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, Detroit, MI 48201

ABSTRAKT

Maspin, a class II tumor suppressor, is often downregulated during tumor progression and its depletion from the nucleus is associated with poor prognosis. Recently, we reported that reintroduction of maspin is sufficient for redifferentiation of prostate cancer cells to epithelial phenotype, a reversal of epithelial-to-mesenchymal transition. We have linked this effect of maspin with its ability to directly inhibit HDAC1, thereby influencing the acetylation state of transcription factors and other proteins. Maspin overexpression leads to changes in the expression level of a large number of proteins and these changes are often microenvironment specific. In this review, we summarize the epigenetic effects of maspin and provide comprehensive bioinformatic analysis of microarray-derived gene expression changes caused by maspin in different microenvironments. The analysis was performed on multiple levels, including identification of statistically enriched gene ontology groups, detection of overreprepresented transcription factors binding sites in promoters of differentially expressed genes, followed by searching for key nodes of regulatory networks controlling these transcription factors. The results are consistent with our hypothesis that maspin serves as an endogenous regulator of HDAC activity and suggest that the effect of maspin is primarily mediated by TGFβ, β-catenin/E-cadherin pathways, and network key nodes such as Abl kinase, p62, IL1, and caspases 6 and 8.