The Roles Of CUEDC2 And SOX4 In The Regulation Of Tumor Cell Growth

In this work,we study the roles of CUEDC2 and SOX4 in regulating the growth of tumor cells,and our findings provide novel function of these proteins.(1) CUEDC2 is a CUE domain-contained gene,whose function is not clear. Identified as ubiquitin binding motifs,the CUE domains are small, moderately-conserved domains of about 40 amino acid residues that are found in a variety of eukaryotic proteins.CUE domains interact with both mono- and poly-ubiquitin,and have a dual role in mono- and poly-ubiquitin recognition as well as in facilitating intramolecular monoubiquitination.Based on the finding that CUEDC2 interacts with progesterone receptor(PR) and promotes progesterone-dependent PR degradation by the ubiquitin-proteasome pathway,we further investigate the regulation of estrogen receptorα(ERα) function by CUEDC2.In this study,we identified that CUEDC2 interacts with ERαand promotes ERαdegradation through the ubiquitin-proteasome pathway in a ligand independent manner.Assessment of ERαlevels in the MCF-7/Control shRNA and MCF-7/CUE shRNA cells demonstrated that knocking down CUEDC2 is associated with increased ERαexpression level.We also show that CUEDC2 represses the transcription of ERαtarget genes,and chromatin immunoprecipitation assays further demonstrate that CUEDC2 associates with the reduced occupancy of ERαto ERE.In concern with these results,we show that CUEDC2 inhibites estrogen-mediated proliferation of breast cancer cells.These findings provide evidence that CUEDC2 promotes the ubiquitination and degradation of ERα,inhibits its transcriptional activity and that this protein is of importance in regulating the growth of breast cancer cells.(2) SOX4 plays important roles in many developmental processes,such as embryonic cardiac development,thymocyte development and nervous system development.Recently,increasing evidence has shown that SOX4 is highly up-regulated in a number of tumors and correlates with better survival in some tumor patients.However,the precise mechanism by which SOX4 is involved in tumorigenesis remains largely unknown.Here we show that SOX4 protein level is elevated following DNA damage treatment.Notably,knocking down of endogenous SOX4 by RNA interfering inhibits the stabilization and activation of p53 tumor suppressor in response to DNA damage.SOX4 interacts with p53 under normal conditions and DNA damage signals enhance their interaction.SOX4 stabilizes p53 protein by blocking Mdm2-mediated p53 ubiquitination and degradation.Furthermore,SOX4 enhances p53 acetylation by interacting with p300/CBP and facilitating p300/CBP/p53 complex formation.Thus,SOX4 may be a novel critical protein involved in the regulation of p53 stability and activity upon DNA damage.In conclusion,our findings provide insight into the roles of SOX4 in the complicated regulation network of p53 in response to DNA damage,and drugs targeting SOX4 may be a potential anti-cancer therapeutic approach for future studies.