Thesis Type: Doctorate
Institution Of The Thesis: Middle East Technical University, Faculty of Arts and Sciences, Department of Biology, Turkey
Approval Date: 2014
Thesis Language: English
Student: Seda Tunçay Çağatay
Supervisor: AYŞE ELİF ERSON BENSANAbstract:
Metastasis associated protein 1 (MTA1) is a member of the nuclear remodeling and histone deacetylase (NuRD) complex, which is known to repress the expression of several tumor suppressor genes and has been widely linked to tumor metastasis. 15-lipoxygenase-1 (15-LOX-1) is a lipid metabolizing enzyme that has tumor suppressive properties and is silenced by the NuRD complex in colorectal cancer (CRC). We have previously shown that reexpression of 15-LOX-1 inhibited metastasis in CRC, inhibited the inflammatory transcription factor nuclear factor kappa B (NF-κB) and resulted in reduced expression of MTA1 indicating the presence of a cross talk. In this study, we have first investigated the role of MTA1 in CRC. For this, the gene was silenced and overexpressed in the CRC cell line HCT-116. MTA1 overexpression enhanced metastasis and epithelial mesenchymal transition (EMT) like characteristics of the cells while silencing of MTA1 resulted in reversal of these features.Reexpression of 15-LOX-1 in CRC cell lines HT-29 and LoVo resulted in decreased expression of MTA1. This was due to a decrease in the nuclear levels and the recruitment of p65 to its binding motifs on the MTA1 promoter as well as inhibition of transcriptional activity of NF-κB. As a conclusion, this study not only shows the protumorigenic properties of MTA1 in CRC but also identifies a novel regulatory mechanism by 15-LOX-1 thereby providing a rationale for the development of anti-metastatic intervention strategies targeting MTA1 or 15-LOX-1 expressions.