Human Cancer Biology Aberrant Methylation of the X-Linked Ribosomal S6 Kinase RPS6KA6 (RSK4) in Endometrial Cancers

Purpose: Effective treatments for advanced endometrial cancer are lacking. Novel therapies that target specific pathways hold promise for better treatment outcomes with less toxicity. Mutation activation of the FGFR2/ RAS/ERK pathway is important in endometrial tumorigenesis. RPS6KA6 (RSK4) is a putative tumor suppressor gene and is a target of the ERK signaling pathway. We explored the role of RSK4 in endometrial cancer. Experimental Design:We showed that RSK4 is expressed in normal endometrial tissue and is absent or much reduced in endometrial cancer. On the basis of previous reports on methylation in other cancers, we hypothesized that the absence of RSK4 transcript is associated with epigenetic silencing rather than mutation. We determined the methylation and expression status of RSK4 in primary endometrial cancers and cell lines and the effects of treatment with a demethylating agent. The relationship between RSK4 methylation and clinicopathologic features was assessed. Results: RSK4 is frequentlyhypermethylated in endometrial cancer cells lines and inprimary endometrial cancer comparedwithnormal endometrial tissue.RSK4methylationwas significantly associatedwith tumor grade,withhigher grade tumorshaving lower levels ofmethylation (P1⁄40.03).RSK4methylation levelswere not associated with other clinical variables. We did find that RSK4methylation was significantly correlated with expression in primary endometrial tumors and in cell lines. Reactivation of RSK4 by 5-azacytidine was successfully performed showing 8to more than 1,200-fold increases in transcript levels. Conclusion: RSK4 appears to be epigenetically silenced in endometrial cancer as evidenced by hypermethylation. Its role as a suppressor in endometrial cancer, however, remains uncertain. Clin Cancer Res; 17(8); 2120–9. 2011 AACR.