HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program

作     者：Ming Huang Wen Dong Ruihui Xie Jilin Wu Qiao Su Wuguo Li Kai Yao Yuelong Chen Qianghua Zhou Qiang Zhang Wenwen Li Liang Cheng Shengmeng Peng Siting Chen Jian Huang Xu Chen Tianxin Lin 

作者机构：Department of UrologySun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouGuangdong 510120P.R.China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene RegulationSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouGuangdong 510120P.R.China Guangdong Provincial Clinical Research Center for Urological DiseasesGuangzhouGuangdong 510120P.R.China Animal Experiment CenterThe First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China Department of UrologySun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China 

出 版 物：《Cancer Communications》 (癌症通讯（英文）)

年 卷 期：2022年第42卷第5期

页      面：447-470页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：National Key Research and Development Program of China,Grant/Award Number:2018YFA0902803 National Natural Science Foundation of China,Grant/Award Numbers:81825016,82072827,81961128027,81702523,81972383,82102957 Guangdong Basic and Applied Basic Research Foundation,Grant/Award Numbers:2021B1515020009,2020A1515010888,2019A1515010188 Science and Technology Program of Guangzhou,Grant/Award Number:202102010002 Guangdong Special Support Program,Grant/Award Number:2017TX04R246 Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(for Tianxin Lin) Guangdong Provincial Clinical Research Center for Urological Diseases,Grant/Award Number:2020B1111170006 Guangdong Science and Technology Department,Grant/Award Numbers:2020B1212060018,2018B030317001 

主　　题：HSF1 PRMT5 KRIBB11 transcriptional program bladder cancer lymphatic metastasis prognostic factor targeted therapy 

摘      要：Background:Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic *** evidence shows that heat shock factor 1(HSF1)drives diversified transcriptome to promote tumor growth and serves as a promising therapeutic ***,the roles of HSF1 in lymphatic metastasis remain largely ***,we aimed to illustrate the clinical roles and mechanisms of HSF1 in the lymphatic metastasis of bladder cancer and explore its therapeutic ***: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 *** in vitro and in vivo assays were performed in HSF1-silenced and-regained *** 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 *** pharmacological inhibitor of HSF1,KRIBB11,was evaluated in popliteal lymph node metastasis models and patientderived xenograft models of bladder ***:HSF1 expression was positively associated with lymphatic metastasis status,tumor stage,advanced grade,and poor prognosis of bladder ***,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 ***,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 me