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
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.
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.
