摘要
Though promoting ferroptosis can reduce cisplatin resistance in tumor cells,ferroptosis and cisplatin resistance in bladder urothelial carcinoma(BUC)following long non-coding RNAs(lncRNAs)is largely unknown.Here,we found the highly expressed lncRNA MAF transcription factor G antisense RNA 1(MAFG-AS1)in BUC,and its inhibition increased the sensitivity of BUC cells to cisplatin by promoting ferroptosis.Mechanically,binding to iron chaperone poly(rC)-binding protein 2(PCBP2)facilitated the recruitments of MAFG-AS1 to deubiquitinase ubiquitin carboxyl-terminal hydrolase isozyme L5(UCHL5),thus stabilizing PCBP2 protein itself.Then PCBP2 was confirmed to interact with ferroportin 1(FPN1),an iron export protein,leading to inhibition of ferroptosis.Moreover,the expression of MAFG-AS1 was regulated by the transcriptional factor MAFG.Interestingly,MAFG-AS1 stimulated MAFG transcription by recruiting histone acetyltransferase p300(EP300)to promote the histone 3 at lysine 27(H3K27ac)at genomic locus of MAFG,forming a MAFG-AS1/MAFG positive feedback loop.In patient samples,higher expression of MAFG-AS1 and MAFG in BUC tissues was significantly correlated with T status and N status,such that MAFG-AS1,MAFG,and the combination of the two were independent prognostic indicators and chemotherapy sensitivity predictive biomarkers for BUC patients.These findings suggest that inhibition of MAFG-AS1 and MAFG can increase the sensitivity of BUC cells to cisplatin through promoting ferroptosis,indicating the novel chemotherapy sensitivity biomarkers and therapeutic target for BUC.
促进铁死亡可以降低肿瘤细胞对顺铂的耐药性,长链非编码RNA(lnc RNA)参与铁死亡的调控,但lnc RNA在调控铁死亡介导的膀胱癌顺铂耐药性中的作用尚不清楚.本研究通过体内外实验,综合运用Ch IP、CO-IP、Ch IRP、PRM-MS等实验及多种生物信息学技术探究了lnc RNA MAFG-AS1调控铁死亡影响膀胱癌顺铂耐药性的作用及具体机制.研究结果发现活化的MAFG-AS1/MAFG正反馈环可通过拮抗铁死亡增加膀胱癌的顺铂耐药性.MAFG-AS1和MAFG可作为膀胱癌的潜在治疗新靶点及化疗敏感性评估标志物.
作者
Liang Xiang
Qinghai Zeng
Jianye Liu
Mengqing Xiao
Dong He
Qun Zhang
Dan Xie
Minhua Deng
Yuxing Zhu
Yan Liu
Hao Bo
Xiaoming Liu
Ming Zhou
Wei Xiong
Yanhong Zhou k
Jianda Zhou
Xiaohui Li
Ke Cao
向亮;曾庆海;刘建业;肖梦卿;何东;张群;谢丹;邓敏华;朱煜星;刘彦;孛昊;刘晓明;周鸣;熊炜;周艳宏;周建大;李晓辉;曹科(Department of Oncology,Third Xiangya Hospital of Central South University,Changsha 410013,China;Department of Dermatology,Third Xiangya Hospital of Central South University,Changsha 410013,China;Department of Urology,Third Xiangya Hospital of Central South University,Changsha 410013,China;Department of Respiratory,The Second People’s Hospital of Hunan Province,Changsha 410007,China;Department of Radiotherapy,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou 510080,China;Department of Pathology,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;Department of Urology,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;Department of Plastic Surgery,Third Xiangya Hospital of Central South University,Changsha 410013,China;Institute of Reproductive and Stem Cell Engineering,Central South University,Changsha 410083,China;Department of Gastroenterology,Third Xiangya Hospital of Central South University,Changsha 410013,China;Cancer Research Institute and Key Laboratory of Carcinogenesis of the Chinese Ministry of Health,Central South University,Changsha 410078,China;Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples,Changsha 410205,China;Department of Pharmaceutical Chemistry,School of Pharmaceutical Sciences,Central South University,Changsha 410013,China)
基金
This work was supported by the National Natural Science Foundation of China(81874137)
the Outstanding Youth Foundation of Hunan Province(2018JJ1047)
the Huxiang Young Talent Project(2016RS3022)
the Hunan Province Science and Technology Talent Promotion Project(2019TJ-Q10)
the Project of Scientific Research Plan of Health and Family Planning Commission of Hunan Province(c20180476)
the Fundamental Research Funds for the Central South University(2018zzts938)
the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hosipital of Central South University(ZC060001 and YX202007).
