The Roles Of Histone Methyltransferases SETD3 In Cell Cycle And Liver Carcinogenesis

Many methyltransferases have critical roles in various biological processes,and their dysregulation is associated with cancer.SETD 3 is one of histone methyltransferases(HMTase)containinga conserved SET(Su(var)3-9,Enhancer-of-zeste and Trithorax)domain,which are able to catalyze histone methylation.However,the functions of SETD3 are still unclear.In our research,we as the first time found that the protein levels of SETD3 flutuate with the cell cycle.SETD3 protein levelare lowest at the M phase and are highest at the S phase.The deficiency of SETD3 can cause cell cycle arrest and reduce the speed of cell proliferation.Thus,SETD3 acts as a cell cycle dependent HMTase which regulates cell cycle progression.Next,we want to explore the regulatory mechanism of SETD3 during cell cycle progression.We found the ?-isoform of a tumor suppressor Fbw7? specifically mediates the degradation of SETD3 through a poly-ubiquitinated modification.A noncanonical Cdc4 phosphodegron phosphorylated by the kniase GSK3? was identified and it was required for priming SETD3 for Fbw7?-mediated recognition and degradation.Depletion or inhibition of GSK3? or Fbw7? resulted in elevated SETD3 levels and delayed S phase progression.These data elucidated that a GSK3?-Fbw7?dependent mechanism controls SETD3 protein level during the cell cycle.SETD3 protein levels affect not only cell cycle but also cell proliferation.The results of examining SETD3 protein level in human cells and tissues showed that SETD3 expressions are dependent ontissueand cell lineage specificity.Cell growth and clone formation assays showed that SETD3 promotes cell proliferation in liver cancer cells.Furthermore,we showed that the SETD3 protein levels correlated with liver tumorigenesis and high malignancy of the clinical tumor samples,The xenograftexperiment showed the oncogenicity of SETD3 exogenous expression of Fbw7? significantly compromise the tumorigenic effects.In conclusion,our results establish that SETD3 is a potential liver cancer biomarker and drug targets that regulated by SCF-FBXW7? complex during its dynamic cell cycle progression.