Casein kinase 2α mediates NCoR1-dependent transcriptional repression of anti-metastasis gene

Dept. of Medical Science/박사[한글] [영문]Nuclear receptor co-repressor 1 (NCoR1) encodes a protein that represses the expression of the targeted genes by HDACs-related promoting chromatin condensation and play important roles in different biological processes including proliferation, differentiation, and development. However, the roles of post-translational modification of NCoR1 have not yet been clearly demonstrated.This study showed that the C-terminus nuclear hormone receptor interacting domain (NRID) of NCoR1 directly interacts with protein kinase Casein Kinase 2 alpha (CK2?) in vitro and in vivo. Furthermore, mutational analysis and in vitro kinase assay revealed that serine 2436 is a major site of phosphorylation of NCoR1. Peptide competition assay and Duolink in situ PLA analysis further confirmed CK2?-dependent phosphorylation of NCoR1 with anti-phosphorylated NCoR1 antibody. In addition, CK2?-dependent phosphorylation stabilized NCoR1 from ubiquitination-dependent proteasome machinery. Importantly, expression levels of NCoR1 were elevated in HCE4 cells to a similar degree as CK2?, and significantly correlated with the invasion activity of HCE4 cells. More importantly siRNA-coupled cDNA microarray experiments showed that both CK2? and NCoR1 cooperatively regulate the transcription of an anti-tumorigenesis gene, CXCL10/IP-10. Therefore, NCoR1 modulates the invasiveness of cancer cells via repression of CXCL10 in a CK2?-dependent manner. Finally, clinical data from endometrial and prostate cancer tissues clearly supported the hypothesis that NCoR1 promotes oncogenesis of prostate cancer via repression of an anti-metastatic gene, CXCL10 in a CK2?-dependent manner. These data demonstrated that the CK2?-dependent phosphorylation stabilized NCoR1, regulated the transcriptional repression activity of NCoR1 protein, and thereby affected the tumorigenesis of human cancers.prohibitio