The Regulatory Mechanisms Controlling Rip3 Expression In Cancer Cells And The Role Of RIP3-midiated Necroptosis In Tumorigenesis

Necrosis is a type of cell death that is morphologically characterized by organelle swelling and plasma membrane rupture.programed necrosis or necroptosis has been identified as a form of regulated that can be induced by a variety of initiators,including death ligands(TNF?,TRAIL,and FasL),interferons,Toll like receptors ligands and certain pathogen infection.Receptor-interacting protein 3(RIP3)is considered as a central signal-transducing component in necroptosis.It has been shown that the expression of RIP3 is silenced in most cancer cells and tissues due to genomic methylation.RIP3-null cancer cells are resistant to these necroptotic stimuli.However,the regulatory mechanisms controlling RIP3 expression in cancer cells and the role of RIP3-midiated necroptosis in tumorigenesis have not been fully elucidated.Here,we report that Sp1,a well-characterized zinc-finger transcription factor,directly regulates RIP3 expression in cancer cells.Knockdown of endogenous Sp1 significantly decreases the transcription of Rip3,thereby further inhibiting necroptosis.The re-expression of wild-type Sp1 restores the necroptotic response.In addition,Knockdown of epigenetic regulator UHRF1 in RIP3-null cancer cells reduces the methylation level of the Rip3 promoter.This effect is sufficient to trigger the expression of RIP3 in RIP3-null cancer cells.The induced expression of RIP3 by UHRF1 RNAi depends on the presence of Sp1.Inhibition of histone deacetylation has no impact on regulating RIP3 expression.Remarkably,the ectopic expression of RIP3 in RIP3-null cancer cells results in a decrease in tumor growth in mice.Therefore,our findings offer insights into RIP3 expression control in cancer cells and suggest an inhibitory effect of RIP3 on tumorigenesis.