Septin 9 hypermethylation contributes to migration and resistance to drug treatments in colon cancer

Abstract

Purpose: To examine septin 9 gene-promoter methylation content in colorectal cancer and establish its significance in cancer progression and chemoresistance. Methods: Patient samples and colorectal cancer cell lines (CRC) were evaluated for septin 9 expression and promoter hypermethylation content. Septin 9 promoter methylation and expression in cells were perturbed by 5-AZA (5-aza-2'-deoxycytidine) treatments or overexpression and probed for changes in Rho A signaling, cell proliferation, and migration. Finally, the significance of septin 9 methylation in chemoresistance was probed using apoptotic assays in CRC cells and in a xenograft tumor model. Results: Expression analysis showed a reduction in septin 9 levels in tumor tissues (p < 0.001) and cell lines (p < 0.01), while an increase in septin 9 promoter methylation was seen, respectively (> 2-fold; p < 0.01). Increasing septin 9 levels in CRC cells by 5-AZA treatments or overexpression showed decreased Rho A signaling and cell migration (p < 0.01), whereas cell proliferation remained unaffected. Furthermore, increasing septin 9 levels also exhibited increased cisplatin-induced apoptosis in CRC cells and reduced chemoresistance in the mouse (~2-fold; p < 0. 01). Conclusion: Septin 9 promoter hypermethylation reduces septin 9 expression and promotes migration and chemoresistance.