RSF1 is a positive regulator of NFkappaB-induced gene expression required for ovarian cancer chemoresistance
Menée sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer de l'ovaire et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de gènes dépendant de la signalisation NFkappaB, l'expression du gène RSF1 contribue au développement d'une résistance au paclitaxel
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 ovarian cancer patients and mouse xenograft model. In addition, RSF1 overexpressing paclitaxel-resistant ovarian cancer cell lines were found to express elevated levels of genes regulated by NFkappaB, including some involved with evasion of apoptosis (CFLAR, XIAP, BCL2, and BCL2L1) and inflammation (PTGS2). Additionally, ectopic expression of RSF1 using tet-off inducible SKOV3 cells significantly enhanced NFkappaB-dependent gene expression and transcriptional activation of NFkappaB. A RSF1 knockdown using shRNAs suppressed these same pathways. Moreover, pretreatment with NFkappaB inhibitors or down-regulation of NFkappaB-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 NFkappaB and CREB-binding protein (CBP), a ubiquitous coactivator for NFkappaB. Recruitment of RSF1 to the NFkappaB binding element in the PTGS2 and XIAP promoters was demonstrated by chromatin immunoprecipitation assay. Furthermore, hSNF2H, a well-known binding partner of RSF1, was partially involved in the interaction between RSF1 and NFkappaB. Taken together, these data suggest that RSF1 may function as a coactivator for NFkappaB, consequently augmenting expression of genes necessary for the development of chemoresistance in ovarian cancer cells.