The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised t...The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised tumors, and may be a useful animal model for the evaluation of various therapeutic approaches for gliosarcomas. In this study, the 9L/Wistar rat glioma model was produced by intracerebral implantation of 9L^LUC glioma cells syngenic to Fischer 344 （F344） rats. Bioluminescence imaging showed that tumors progressively grew from day 7 to day 21 in 9L^LUC/F344 rats, and tumor regression was found in some 9L^LUC/Wistar rats. Hematoxylin-eosin staining verified that intracranial tumors were gliomas. Immunohistochemistry results demonstrated that no CD4- and CD8-positive cells were found in the syngeneic 9L^LUC/F344 model. However, many infiltrating CD4- and CD8-positive cells were observed within the tumors of the 9L^LUC/Wistar model. Our data suggests that compared with 9L/F344 rats, 9L glioma Wistar rats may not be suitable for evaluating brain glioma immunotherapies, even though the model induced an immune response and exhibited tumor regression.展开更多
Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acety...Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acetyltransferase 1(HAT1)confers reprogramming of gluconeogenesis/lipogenesis in liver cancer.Diethylnitrosamine(DEN)/carbon tetrachloride(CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice.Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver.Protein phosphatase 2 scaffold subunit alpha(PPP2R1A)promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1(PCK1)serine 90 dephosphorylation to suppress the tumor growth.HAT1 succinylated PPP2R1A at lysine 541(K541)to block the assembly of protein phosphatase 2A(PP2A)holoenzyme and interaction with PCK1,resulting in the depression of dephosphorylation of PCK1.HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation,leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1(SREBP1)nuclear accumulation-induced lipogenesis gene expression,which enhanced the tumor growth.In conclusion,succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer.Our finding provides new insights into the mechanism by which post-translational modifications(PTMs)confer the conversion of tumor suppressor function to oncogene.展开更多
Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrat...Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.展开更多
文摘The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised tumors, and may be a useful animal model for the evaluation of various therapeutic approaches for gliosarcomas. In this study, the 9L/Wistar rat glioma model was produced by intracerebral implantation of 9L^LUC glioma cells syngenic to Fischer 344 （F344） rats. Bioluminescence imaging showed that tumors progressively grew from day 7 to day 21 in 9L^LUC/F344 rats, and tumor regression was found in some 9L^LUC/Wistar rats. Hematoxylin-eosin staining verified that intracranial tumors were gliomas. Immunohistochemistry results demonstrated that no CD4- and CD8-positive cells were found in the syngeneic 9L^LUC/F344 model. However, many infiltrating CD4- and CD8-positive cells were observed within the tumors of the 9L^LUC/Wistar model. Our data suggests that compared with 9L/F344 rats, 9L glioma Wistar rats may not be suitable for evaluating brain glioma immunotherapies, even though the model induced an immune response and exhibited tumor regression.
基金supported by the National Natural Science Foundation of China(Nos.82103066,82372818,82303210,and 82302887)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A,China).
文摘Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acetyltransferase 1(HAT1)confers reprogramming of gluconeogenesis/lipogenesis in liver cancer.Diethylnitrosamine(DEN)/carbon tetrachloride(CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice.Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver.Protein phosphatase 2 scaffold subunit alpha(PPP2R1A)promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1(PCK1)serine 90 dephosphorylation to suppress the tumor growth.HAT1 succinylated PPP2R1A at lysine 541(K541)to block the assembly of protein phosphatase 2A(PP2A)holoenzyme and interaction with PCK1,resulting in the depression of dephosphorylation of PCK1.HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation,leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1(SREBP1)nuclear accumulation-induced lipogenesis gene expression,which enhanced the tumor growth.In conclusion,succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer.Our finding provides new insights into the mechanism by which post-translational modifications(PTMs)confer the conversion of tumor suppressor function to oncogene.
基金supported by the National Natural Science Foundation of China(Nos.82372818 to Xiaodong Zhang,82103066 to Guang Yang,82302887 to Hongfeng Yuan,82303210 to Yufei Wang)The China Postdoctoral Science Foundation(No.2022M712389 to Hongfeng Yuan,No.2023M732624 to Yufei Wang,No.2023M742621 to Lina Zhao)+1 种基金Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A to W.Lu,China)“14th Five-Year Plan”Tumor Prevention and Treatment Research Project of Tianjin Medical University Cancer Institute and Hospital(No.YZ-03,China).
文摘Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.
