Enhancer RNAs(eRNAs),a subclass of non-coding RNAs transcribed from enhancer regions,have emerged as critical regulators of gene expression;however,their functional roles in prostate cancer remain largely unexplored.I...Enhancer RNAs(eRNAs),a subclass of non-coding RNAs transcribed from enhancer regions,have emerged as critical regulators of gene expression;however,their functional roles in prostate cancer remain largely unexplored.In this study,we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues.By incorporating chromatin immunoprecipitation sequencing data,we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways.Among these,lactotransferrin-eRNA(LTFe)was markedly downregulated in prostate cancer tissues,with functional analyses revealing its tumor-suppressive role.Mechanistically,LTFe promotes the transcription of its target gene,lactotransferrin(LTF),by interacting with heterogeneous nuclear ribonucleoprotein F(HNRNPF)and facilitating enhancer-promoter chromatin interactions.Furthermore,we demonstrate that the LTFe-LTF axis facilitates ferroptosis by modulating iron transport.Notably,androgen receptor(AR)signaling disrupts LTFe-associated chromatin looping,leading to ferroptosis resistance.Therapeutically,co-administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth,offering a promising strategy for castrationresistant prostate cancer.Collectively,this study provides novel insights into the mechanistic role of eRNAs in prostate cancer,highlighting the LTFe-LTF axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82373333,82173068)to Z.Wang,and Nos.82073082,82311530050 to G.-H.Wei+2 种基金the Hubei Natural Science Foundation Innovation Development Joint Fund Key Project(2024AFD420 to Z.Wang)the National Key Research and Development Program of China(2022YFC2703600 to G.-H.Wei)Z.X.Wang was supported by the National Natural Science Foundation of China(82203416)。
文摘Enhancer RNAs(eRNAs),a subclass of non-coding RNAs transcribed from enhancer regions,have emerged as critical regulators of gene expression;however,their functional roles in prostate cancer remain largely unexplored.In this study,we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues.By incorporating chromatin immunoprecipitation sequencing data,we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways.Among these,lactotransferrin-eRNA(LTFe)was markedly downregulated in prostate cancer tissues,with functional analyses revealing its tumor-suppressive role.Mechanistically,LTFe promotes the transcription of its target gene,lactotransferrin(LTF),by interacting with heterogeneous nuclear ribonucleoprotein F(HNRNPF)and facilitating enhancer-promoter chromatin interactions.Furthermore,we demonstrate that the LTFe-LTF axis facilitates ferroptosis by modulating iron transport.Notably,androgen receptor(AR)signaling disrupts LTFe-associated chromatin looping,leading to ferroptosis resistance.Therapeutically,co-administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth,offering a promising strategy for castrationresistant prostate cancer.Collectively,this study provides novel insights into the mechanistic role of eRNAs in prostate cancer,highlighting the LTFe-LTF axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes.
