Emerging evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) is strongly associated with the occurrence and progression of breast cancer. Herein, we identified ubiquitin specific peptidase 30 ...Emerging evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) is strongly associated with the occurrence and progression of breast cancer. Herein, we identified ubiquitin specific peptidase 30 antisense RNA 1 (USP30-AS1) as a markedly upregulated lncRNA in breast cancer tissues, and the transcription factor SPI1 functions upstream to regulate the expression of USP30-AS1. Gene set enrichment analysis suggests that USP30-AS1 may regulate cell proliferation. Knockdown of USP30-AS1 suppresses breast cancer cell proliferation and tumor growth by up-regulating CDKN1A/p21. Mechanistically, USP30-AS1 exhibits dual localization within breast cancer cells. In the cytoplasm, it interacts with HnRNPF, disrupting its binding to the p21 3′UTR, which destabilizes p21 mRNA and ultimately reduces p21 expression. In the nucleus, USP30-AS1 suppresses p21 transcription by enhancing the activity of c-Myc, a known transcriptional repressor of p21. USP30-AS1 binds to enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, and prevents EZH2 from binding to the c-Myc promoter. This promotes epigenetic up-regulation of c-Myc by reducing H3K27 trimethylation. Together, these findings demonstrate the critical role of USP30-AS1 in breast cancer progression through HnRNPF/p21 and EZH2/c-Myc/p21 axes, highlighting its potential as a therapeutic target for breast cancer treatment.展开更多
Background:Alzheimer’sdisease(AD)is a prevalent neurodegenerative disorder causing progressive dementia.Research suggests that microRNAs(miRNAs)could serve as biomarkers and therapeutic targets for AD.Reduced levels ...Background:Alzheimer’sdisease(AD)is a prevalent neurodegenerative disorder causing progressive dementia.Research suggests that microRNAs(miRNAs)could serve as biomarkers and therapeutic targets for AD.Reduced levels of miR-137 have been observed in the brains of AD patients,but its specific role and down stream mechanisms remain unclear.This study sought to examine the therapeutic potential of miR-137-5p agomir in alleviating cognitive dysfunction induced in AD models and explore its potential mechanisms.Methods:This study utilized bioinformatic analysis and a dual-l uciferase reporter assay to investigate the relationship between miR-137-5p and ubiquitin-specific peptidase 30(USP30).In vitro experiments were conducted using SH-SY5Y cells to assess the impact of miR-137-5p on Aβ1-42 neurotoxicity.In vivo experiments on AD mice evaluated the effects of miR-137-5p on cognition,Aβ1-42 deposition,Tau hyperphosphorylation,and neuronal apoptosis,as well as its influence on USP30 levels.Results:It was discovered that miR-137-5p mimics efficiently counteract Aβ1-42 neurotoxicity in SH-SY5Y cells,a protective effect that is negated by USP30 overexpression.In vivo experiments demonstrated that miR-137-5p enhances the cognition and mobility of AD mice,significantly reducing Aβ1-42 deposition,Tau hyperphosphorylation,and neuronal apoptosis within the hippocampus and cortex regions.Mechanistically,miR-137-5p significantly suppresses USP30 levels in mice,though USP30 overexpression partially buffers against miR-137-5p-i nduced AD symptom improvement.Conclusion:Our study proposes that miR-137-5p,by instigating the downregulation of USP30,has the potential to act as a novel and promising therapeutic target for AD.展开更多
基金supported the National Key R&D Program of China(No.2023YFA0914300,2023YFA0914302)the National Natural Science Foundation of China(No.31571418,32200438)+1 种基金the Shenzhen Science and Technology Innovation Commission(No.JCYJ20160226185623304,JCYJ20240813142003005)Henan Provincial Science and Technology Research Project(No.252102310403).
文摘Emerging evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) is strongly associated with the occurrence and progression of breast cancer. Herein, we identified ubiquitin specific peptidase 30 antisense RNA 1 (USP30-AS1) as a markedly upregulated lncRNA in breast cancer tissues, and the transcription factor SPI1 functions upstream to regulate the expression of USP30-AS1. Gene set enrichment analysis suggests that USP30-AS1 may regulate cell proliferation. Knockdown of USP30-AS1 suppresses breast cancer cell proliferation and tumor growth by up-regulating CDKN1A/p21. Mechanistically, USP30-AS1 exhibits dual localization within breast cancer cells. In the cytoplasm, it interacts with HnRNPF, disrupting its binding to the p21 3′UTR, which destabilizes p21 mRNA and ultimately reduces p21 expression. In the nucleus, USP30-AS1 suppresses p21 transcription by enhancing the activity of c-Myc, a known transcriptional repressor of p21. USP30-AS1 binds to enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, and prevents EZH2 from binding to the c-Myc promoter. This promotes epigenetic up-regulation of c-Myc by reducing H3K27 trimethylation. Together, these findings demonstrate the critical role of USP30-AS1 in breast cancer progression through HnRNPF/p21 and EZH2/c-Myc/p21 axes, highlighting its potential as a therapeutic target for breast cancer treatment.
基金Liaoning Province Science and Technology Project(grant/award number:2019-BS-221)Shenyang Science and Technology Project(grant/award number:19-112-4-040)。
文摘Background:Alzheimer’sdisease(AD)is a prevalent neurodegenerative disorder causing progressive dementia.Research suggests that microRNAs(miRNAs)could serve as biomarkers and therapeutic targets for AD.Reduced levels of miR-137 have been observed in the brains of AD patients,but its specific role and down stream mechanisms remain unclear.This study sought to examine the therapeutic potential of miR-137-5p agomir in alleviating cognitive dysfunction induced in AD models and explore its potential mechanisms.Methods:This study utilized bioinformatic analysis and a dual-l uciferase reporter assay to investigate the relationship between miR-137-5p and ubiquitin-specific peptidase 30(USP30).In vitro experiments were conducted using SH-SY5Y cells to assess the impact of miR-137-5p on Aβ1-42 neurotoxicity.In vivo experiments on AD mice evaluated the effects of miR-137-5p on cognition,Aβ1-42 deposition,Tau hyperphosphorylation,and neuronal apoptosis,as well as its influence on USP30 levels.Results:It was discovered that miR-137-5p mimics efficiently counteract Aβ1-42 neurotoxicity in SH-SY5Y cells,a protective effect that is negated by USP30 overexpression.In vivo experiments demonstrated that miR-137-5p enhances the cognition and mobility of AD mice,significantly reducing Aβ1-42 deposition,Tau hyperphosphorylation,and neuronal apoptosis within the hippocampus and cortex regions.Mechanistically,miR-137-5p significantly suppresses USP30 levels in mice,though USP30 overexpression partially buffers against miR-137-5p-i nduced AD symptom improvement.Conclusion:Our study proposes that miR-137-5p,by instigating the downregulation of USP30,has the potential to act as a novel and promising therapeutic target for AD.
