Date

2013-09-01

Author

ÇAĞATAY, SİBEL
Banerjee, Sreeparna

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Background: Metastasis Associated Protein 1 (MTA1) is a member of the nuclear remodeling and histone deacetylase (NuRD) complex that is known to repress the expression of several tumor suppressor genes. 15-lipoxygenase-1 (15-LOX-1), a member of the inflammatory eicosanoid pathway, has been shown by us and others to have an anti-tumorigenic role in colon cancer. ALOX15 was recently shown to be repressed by the NuRD complex. Previously we have reported that ectopic expression of 15-LOX-1 in colon cancer cells reduced MTA1 expression, indicating the presence of a crosstalk and a negative correlation between 15-LOX-1 and MTA1 expressions. To understand the mechanism behind this crosstalk, we have hypothesized the involvement of nuclear factor kappa B (NF-kB). MTA1 can be transcriptionally upregulated by NF-kB, while we and others have shown that 15-LOX-1 can inhibit the activity of NF-kB. We have ectopically expressed 15-LOX-1 in colon cancer cell lines and examined the expression of MTA1 and NFkB p65 subunit in a panel of 5 colon cancer cell lines and the transcriptional regulation of MTA1 by NF-kB. We have also checked whether there is a correlation between the expression of 15-LOX-1 and MTA1 by analyzing publicly available human colorectal cancer gene expression datasets. Materials and Methods: Cells were transiently transfected a 15-LOX-1 expression vector or the empty vector. Protein levels of 15-LOX-1, MTA1 and NFkB p65 were detected by Western blot analysis. NF-kB recruitment to the promoter of MTA1 was determined by chromatin immunoprecipitation and luciferase assays. Publicly available colorectal cancer dataset GSE41258 was obtained from Gene Expression Omnibus (GEO) and analyzed with GeneSpring GX 11.0. Results: HT-29 and LoVo cells transfected with the 15-LOX-1 vector showed a decrease in nuclear levels of NF-kB p65 and MTA1 expression. Recruitment of p65 onto its consensus sequence at the MTA1 promoter was reduced in 15-LOX-1 expressing cells. Moreover, the expression of MTA1 and 15-LOX-1 was negatively correlated particularly in the Stage 3 and Stage 4 colorectal cancer patients. Conclusion: 15-LOX-1 may inhibit MTA1 expression at least partly via reduced recruitment of NF-kB on to the MTA1 promoter. Based on recent reports by us and others on the role of MTA1 as a master regulator of cellular transformation in several tumor types, these data may help in understanding the regulation of MTA1 and open ways for therapeutic applications in the future.

Subject Keywords

Oncology

URI

https://hdl.handle.net/11511/56029

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Department of Biology, Conference / Seminar