Down-regulation of filamin A interacting protein 1-like is associated with promoter methylation and induces an invasive phenotype in ovarian cancer

• Published in: Molecular cancer research 2011-06, Vol.9 (8), p.1126-1138
• Main Authors: Burton, Elizabeth R., Gaffar, Aneesa, Lee, Soo Jin, Adeshuko, Folashade, Whitney, Kathleen D., Chung, Joon-Yong, Hewitt, Stephen M., Huang, Gloria S., Goldberg, Gary L., Libutti, Steven K., Kwon, Mijung
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-11-0162

Ovarian cancer is the most lethal gynecologic malignancy with a five-year survival rate below 25% for patients with stage III–IV disease. Identifying key mediators of ovarian cancer invasion and metastasis is critical to the development of more effective therapeutic interventions. We previously identified F ilamin A i nteracting p rotein 1 - l ike (FILIP1L) as an important mediator of cell proliferation and migration. In addition, targeted expression of FILIP1L in tumors inhibited tumor growth in vivo . In our present study, we confirmed that both mRNA and protein expression of FILIP1L were down-regulated in ovarian cancer cells compared to normal ovarian epithelial cells. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and clinical ovarian cancer specimens. We also provide evidence that DNA methylation is a mechanism by which FILIP1L is down-regulated in ovarian cancer. The CpG island in the FILIP1L promoter was heavily methylated in ovarian cancer cells. Methylation status of the FILIP1L promoter was inversely correlated with FILIP1L expression in ovarian cell lines and clinical ovarian specimens. Reduced methylation in the FILIP1L promoter following treatment with a DNA demethylating agent was associated with restoration of FILIP1L expression in ovarian cancer cells. A transcription activator, CREB was shown to bind to the CREB/ATF site in the CpG island of the FILIP1L promoter. Overall, these findings suggest that down-regulation of FILIP1L associated with DNA methylation is related with the invasive phenotype in ovarian cancer and that modulation of FILIP1L expression has the potential to be a target for ovarian cancer therapy.