RSF1 Is a Positive Regulator of NF-κB-Induced Gene Expression Required for Ovarian Cancer Chemoresistance

Overexpression or amplification of the RSF1 gene has been associated with poor prognosis in various human cancers, including ovarian cancer. In previous work, RSF1 was identified as an amplified gene that facilitated the development of paclitaxel-resistant ovarian cancer. In the present study, we further demonstrated that RSF1 expression inversely correlated with paclitaxel response in patients with ovarian cancer and the mouse xenograft model. In addition, RSF1-overexpressing paclitaxel-resistant ovarian cancer cell lines were found to express elevated levels of genes regulated by NF-kappa B, including some involved with the evasion of apoptosis (CFLAR, XIAP, BCL2, and BCL2L1) and inflammation (PTGS2). In addition, ectopic expression of RSF1 using Tet-off inducible SKOV3 cells significantly enhanced NF-kappa B-dependent gene expression and transcriptional activation of NF-kappa B. An RSF1 knockdown using short hairpin RNAs suppressed these same pathways. Moreover, pretreatment with NF-kappa B inhibitors or downregulation of NF-kappa B-regulated gene expression considerably enhanced paclitaxel sensitivity in RSF1-overexpressing OVCAR3 and/or RSF1-induced SKOV3 cells. A coimmunoprecipitation assay revealed that RSF1 interacts with NF-kappa B and CREB-binding protein, a ubiquitous coactivator for NF-kappa B. Recruitment of RSF1 to the NF-kappa B binding element in the PTGS2 and XIAP promoters was demonstrated by the chromatin immunoprecipitation assay. Furthermore, hSNF2H, a well-known binding partner of RSF1, was partially involved in the interaction between RSF1 and NF-kappa B. Taken together, these data suggest that RSF1 may function as a coactivator for NF-kappa B, consequently augmenting expression of genes necessary for the development of chemoresistance in ovarian cancer cells. (C) 2014 AACR.