Plant root stem cells and their surrounding microenvironment,namely the stem cell niche,are hypersensitive to DNA damage.However,the molecular mechanisms that help maintain the genome stability of root stem cells rema...Plant root stem cells and their surrounding microenvironment,namely the stem cell niche,are hypersensitive to DNA damage.However,the molecular mechanisms that help maintain the genome stability of root stem cells remain elusive.Here we show that the root stem cells in the skbl（Shk1 kinase binding protein 1） mutant undergoes DNA damage-induced cell death,which is enhanced when combined with a lesion of the Ataxia-telangiectasia mutated（ATM） or the ATM/RAD3-related（ATR） genes,suggesting that the SKBI plays a synergistically effect with ATM and ATR in DNA damage pathway.We also provide evidence that SKBI is required for the maintenance of quiescent center（QC）,a root stem cell niche,under DNA damage treatments.Furthermore,we report decreased and ectopic expression of SHORTROOT（SHR） in response to DNA damage in the skbl root tips,while the expression of SCARECROW（SCR） remains unaffected.Our results uncover a new mechanism of plant root stem cell maintenance under DNA damage conditions that requires SKB1.展开更多
2025年4月5日,上海交通大学医学院附属新华医院检验科郑英霞教授团队在权威期刊Journal for Immunotherapy of Cancer发表题目为“PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synerg...2025年4月5日,上海交通大学医学院附属新华医院检验科郑英霞教授团队在权威期刊Journal for Immunotherapy of Cancer发表题目为“PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy”的研究论文。该研究揭示了蛋白精氨酸甲基转移酶5(protein arginine methyltransferase 5,PRMT5)通过STAT6-PPARγ途径调节脂质代谢,促进单核巨噬细胞的迁移和分化,促进巨噬细胞向M2型极化。在小鼠髓系细胞中特异性敲除Prmt5(Prmt5 cKO)并进行肿瘤模型构建,发现在敲除鼠中肿瘤相关巨噬细胞发生重编程,抗肿瘤活性增强,抑制肿瘤进展并显著增强抗程序性死亡受体配体1(programmed death-ligand 1,PD-L1)的免疫治疗效果。该研究结果提示靶向髓系细胞中的PRMT5有望为癌症免疫治疗提供一种新的方法。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
Background:Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic options.Emerging evidence shows that heat shock factor 1(HSF1)drives diversified transcriptom...Background:Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic options.Emerging evidence shows that heat shock factor 1(HSF1)drives diversified transcriptome to promote tumor growth and serves as a promising therapeutic target.However,the roles of HSF1 in lymphatic metastasis remain largely unknown.Herein,we aimed to illustrate the clinical roles and mechanisms of HSF1 in the lymphatic metastasis of bladder cancer and explore its therapeutic potential.Methods:We screened the most relevant gene to lymphatic metastasis among overexpressed heat shock factors(HSFs)and heat shock proteins(HSPs),and analyzed its clinical relevance in three cohorts.Functional in vitro and in vivo assays were performed in HSF1-silenced and-regained models.We also used Coimmunoprecipitation to identify the binding proteins of HSF1 and chromatin immunoprecipitation and dual-luciferase reporter assays to investigate the transcriptional program directed by HSF1.The pharmacological inhibitor of HSF1,KRIBB11,was evaluated in popliteal lymph node metastasis models and patientderived xenograft models of bladder cancer.Results:HSF1 expression was positively associated with lymphatic metastasis status,tumor stage,advanced grade,and poor prognosis of bladder cancer.Importantly,HSF1 enhanced the epithelial-mesenchymal transition(EMT)of cancer cells in primary tumor to initiate metastasis,proliferation of cancer cells in lymph nodes,and macrophages infiltration to facilitate multistep lymphatic metastasis.Mechanistically,HSF1 interacted with protein arginine methyltransferase 5(PRMT5)and jointly induced the monomethylation of histone H3 at arginine 2(H3R2me1)and symmetric dimethylation of histone H3 at arginine 2(H3R2me2s).This recruited the WD repeat domain 5(WDR5)/mixed-lineage leukemia(MLL)complex to increase the trimethylation of histone H3 at lysine 4(H3K4me3);resulting in upregulation of lymphoid enhancer-binding factor 1(LEF1),matrix metallopeptidase 9(MMP9),C-C motif chemokine ligand 20(CCL20),and E2F transcription factor 2(E2F2).Application of KRIBB11 significantly inhibited the lymphatic metastasis of bladder cancer with no significant toxicity.Conclusion:Our findings reveal a novel transcriptional program directed by the HSF1-PRMT5-WDR5 axis during the multistep process of lymphatic metastasis in bladder cancer.Targeting HSF1 could be a multipotent and promising therapeutic strategy for bladder cancer patients with lymphatic metastasis.展开更多
文摘Plant root stem cells and their surrounding microenvironment,namely the stem cell niche,are hypersensitive to DNA damage.However,the molecular mechanisms that help maintain the genome stability of root stem cells remain elusive.Here we show that the root stem cells in the skbl（Shk1 kinase binding protein 1） mutant undergoes DNA damage-induced cell death,which is enhanced when combined with a lesion of the Ataxia-telangiectasia mutated（ATM） or the ATM/RAD3-related（ATR） genes,suggesting that the SKBI plays a synergistically effect with ATM and ATR in DNA damage pathway.We also provide evidence that SKBI is required for the maintenance of quiescent center（QC）,a root stem cell niche,under DNA damage treatments.Furthermore,we report decreased and ectopic expression of SHORTROOT（SHR） in response to DNA damage in the skbl root tips,while the expression of SCARECROW（SCR） remains unaffected.Our results uncover a new mechanism of plant root stem cell maintenance under DNA damage conditions that requires SKB1.
文摘2025年4月5日,上海交通大学医学院附属新华医院检验科郑英霞教授团队在权威期刊Journal for Immunotherapy of Cancer发表题目为“PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy”的研究论文。该研究揭示了蛋白精氨酸甲基转移酶5(protein arginine methyltransferase 5,PRMT5)通过STAT6-PPARγ途径调节脂质代谢,促进单核巨噬细胞的迁移和分化,促进巨噬细胞向M2型极化。在小鼠髓系细胞中特异性敲除Prmt5(Prmt5 cKO)并进行肿瘤模型构建,发现在敲除鼠中肿瘤相关巨噬细胞发生重编程,抗肿瘤活性增强,抑制肿瘤进展并显著增强抗程序性死亡受体配体1(programmed death-ligand 1,PD-L1)的免疫治疗效果。该研究结果提示靶向髓系细胞中的PRMT5有望为癌症免疫治疗提供一种新的方法。
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.
基金National Key Research and Development Program of China,Grant/Award Number:2018YFA0902803National Natural Science Foundation of China,Grant/Award Numbers:81825016,82072827,81961128027,81702523,81972383,82102957+5 种基金Guangdong Basic and Applied Basic Research Foundation,Grant/Award Numbers:2021B1515020009,2020A1515010888,2019A1515010188Science and Technology Program of Guangzhou,Grant/Award Number:202102010002Guangdong Special Support Program,Grant/Award Number:2017TX04R246Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(for Tianxin Lin)Guangdong Provincial Clinical Research Center for Urological Diseases,Grant/Award Number:2020B1111170006Guangdong Science and Technology Department,Grant/Award Numbers:2020B1212060018,2018B030317001。
文摘Background:Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic options.Emerging evidence shows that heat shock factor 1(HSF1)drives diversified transcriptome to promote tumor growth and serves as a promising therapeutic target.However,the roles of HSF1 in lymphatic metastasis remain largely unknown.Herein,we aimed to illustrate the clinical roles and mechanisms of HSF1 in the lymphatic metastasis of bladder cancer and explore its therapeutic potential.Methods:We screened the most relevant gene to lymphatic metastasis among overexpressed heat shock factors(HSFs)and heat shock proteins(HSPs),and analyzed its clinical relevance in three cohorts.Functional in vitro and in vivo assays were performed in HSF1-silenced and-regained models.We also used Coimmunoprecipitation to identify the binding proteins of HSF1 and chromatin immunoprecipitation and dual-luciferase reporter assays to investigate the transcriptional program directed by HSF1.The pharmacological inhibitor of HSF1,KRIBB11,was evaluated in popliteal lymph node metastasis models and patientderived xenograft models of bladder cancer.Results:HSF1 expression was positively associated with lymphatic metastasis status,tumor stage,advanced grade,and poor prognosis of bladder cancer.Importantly,HSF1 enhanced the epithelial-mesenchymal transition(EMT)of cancer cells in primary tumor to initiate metastasis,proliferation of cancer cells in lymph nodes,and macrophages infiltration to facilitate multistep lymphatic metastasis.Mechanistically,HSF1 interacted with protein arginine methyltransferase 5(PRMT5)and jointly induced the monomethylation of histone H3 at arginine 2(H3R2me1)and symmetric dimethylation of histone H3 at arginine 2(H3R2me2s).This recruited the WD repeat domain 5(WDR5)/mixed-lineage leukemia(MLL)complex to increase the trimethylation of histone H3 at lysine 4(H3K4me3);resulting in upregulation of lymphoid enhancer-binding factor 1(LEF1),matrix metallopeptidase 9(MMP9),C-C motif chemokine ligand 20(CCL20),and E2F transcription factor 2(E2F2).Application of KRIBB11 significantly inhibited the lymphatic metastasis of bladder cancer with no significant toxicity.Conclusion:Our findings reveal a novel transcriptional program directed by the HSF1-PRMT5-WDR5 axis during the multistep process of lymphatic metastasis in bladder cancer.Targeting HSF1 could be a multipotent and promising therapeutic strategy for bladder cancer patients with lymphatic metastasis.
