| E3 ubiquitin ligases which catalyze K48-linked ubiquitination are often involved in proteasome-dependent protein degradation.TRIM11 has E3 ubiquitin ligase activity and is a new oncogene that is highly expressed in various types of tumors.The latest research results suggest dysregulation of enhancers may be one of the key factors in carcinogenesis.KDM5C is a demethylase of histone H3K4me3 and H3K4me2,which regulates histone modification and enhancer activity,and is involved in various biological processes such as gene transcription regulation,chromatin remodeling,ontogeny,and cancer occurrence.Our study identifies TRIM11 as an E3 ubiquitin ligase of KDM5C.TRIM11 interacts with KDM5C,catalyzes its polyubiquitination and promotes KDM5C degradation through proteasome in breast cancer cell.Real time cell analysis(RTCA)and Transwell experiments confirm that TRIM11 promotes the proliferation and migration of breast cancer cells MDA-MB-231 through KDM5C.The result of tumorigenesis in nude mice shows that knockdown of TRIM11 inhibits the formation of subcutaneous tumors,and knockdown of KDM5C is conversely.Immunohistochemistry(IHC)staining finds that TRIM11 is highly expressed and KDM5C is lower expressed in breast cancer patient tissues,and their expression is negatively correlated.In an animal model of breast cancer,TRIM11 deficiency inhibits breast tumor growth and stabilizes KDM5C.The above results demonstrate that TRIM11 promotes breast cancer development by regulating KDM5C stability.To further search for KDM5C target genes,we use RNA-seq and ChIP-seq methods to analyze the gene expression profiles and epigenomics changes in TRIM11 and KDM5C knockdown cell lines as well as TRIM11 knockout mice,respectively.We find that TRIM11 regulates the level of histone H3K4me3 on enhancers and enhancer activity of genes involved in cell migration,lipid metabolism and immune response by targeting KDM5C.The further results show that TRIM 11 targets MCAM enhancer through KDM5C to promote MCAM expression and cell migration.Meanwhile,TRIM11 targets the enhancer of cholesterol efflux gene ABCA1 through KDM5C to suppress ABCA1 expression and regulate lipid metabolism homeostasis in breast tumors.These results reveal novel molecular mechanisms of TRIM11 and KDM5C in regulating the epigenetic status of enhancers in breast cancer cells.In conclusion,our study reveals a new mechanism for enhancer regulation,breast cancer occurrence and development,and provides potential new targets for the diagnosis and treatment of breast cancer patients with high TRIM11 expression or KDM5C mutations. |
