title: Tumor suppressor maspin as a rheostat in HDAC regulation to achieve the fine-tuning of epithelial homeostasis.
abstract: 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.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, Detroit, MI 48201, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kaplun
authors.forename: Sijana
authors.initials: S
authors.lastname: Dzinic
authors.forename: M
authors.initials: M
authors.lastname: Bernardo
authors.forename: Shijie
authors.initials: S
authors.lastname: Sheng
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019295:Computational Biology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C085344:SERPIN-B5; D015843:Serpins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1