Histone methylation plays a crucial role in tumorigenesis.Enhancer of zeste homolog 2(EZH2)is a histone methyltransferase that regulates chromatin structure and gene expression.EZH2 inhibitors(EZH2is)have been shown t...Histone methylation plays a crucial role in tumorigenesis.Enhancer of zeste homolog 2(EZH2)is a histone methyltransferase that regulates chromatin structure and gene expression.EZH2 inhibitors(EZH2is)have been shown to be effective in treating hematologic malignancies,while their effectiveness in solid tumors remains limited.One of the major challenges in the treatment of solid tumors is their hypoxic tumor microenvironment.Hypoxia-inducible factor 1-alpha(HIF-1α)is a key hypoxia responder that interacts with EZH2 to promote tumor progression.Here we discuss the implications of the relationship between EZH2 and hypoxia for expanding the application of EZH2is in solid tumors.展开更多
Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tune...Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.展开更多
基金funded by the National Key Research and Development Program of China(2022YFA1104001 to L.X.)the National Natural Science Foundation of China(82272745 and 81972966 to L.X.,82203433 to Y.W.,82303225 to Y.T.)+1 种基金the Peking University Third Hospital Clinical Key Project(BYSYZD2023010 to L.X.,BYSY2022070 to Y.W.,BYSYZD2023041 and BYSYRCYJ2023004 to J.Z.)the National Institutes of Health(R01 CA107469 and R01 CA125577 to C.G.K.).
文摘Histone methylation plays a crucial role in tumorigenesis.Enhancer of zeste homolog 2(EZH2)is a histone methyltransferase that regulates chromatin structure and gene expression.EZH2 inhibitors(EZH2is)have been shown to be effective in treating hematologic malignancies,while their effectiveness in solid tumors remains limited.One of the major challenges in the treatment of solid tumors is their hypoxic tumor microenvironment.Hypoxia-inducible factor 1-alpha(HIF-1α)is a key hypoxia responder that interacts with EZH2 to promote tumor progression.Here we discuss the implications of the relationship between EZH2 and hypoxia for expanding the application of EZH2is in solid tumors.
基金This work was supported by grants from the National Natural Science Foundation of China(31730026,81930039,and 81525012).
文摘Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.
