{"title":"LncRNA LINC00667通过调节POTEE抑制线粒体氧化磷酸化抑制乳腺癌进展。","authors":"Zhengling Yu , Keying Xu , Yini Shang , Changhui Geng , Youxue Zhang , Lihong Wang","doi":"10.1016/j.cellsig.2025.112074","DOIUrl":null,"url":null,"abstract":"<div><div>Breast cancer (BC) is characterized by significant heterogeneity, which is reflected in genetic mutations and aberrant protein expression. Although long noncoding RNAs (lncRNAs) are known to influence the progression of BC, their regulatory roles in posttranslational modifications remain poorly understood. In this study, we investigated the function of <em>LINC00667</em>, an intergenic lncRNA that is downregulated in BC cell lines and tissues. Our results demonstrate that <em>LINC00667</em> serves as a favorable prognostic marker for breast cancer. Functional characterization revealed that overexpression of <em>LINC00667</em> suppresses malignant progression, while its knockdown promotes oncogenic phenotypes in BC. Mechanistically, we used CHIRP and RIP assays to confirm direct binding interactions between <em>LINC00667</em> and two proteins: ubiquitin B (UBB) and POTE ankyrin domain family member E (POTEE). We found that <em>LINC00667</em> reduces POTEE expression and inhibits mitochondrial oxidative phosphorylation (OXPHOS). Specifically, silencing of POTEE decreased the expression of OXPHOS complexes, an effect that could be rescued by knockdown of <em>LINC00667</em>. Conversely, overexpression of POTEE enhanced OXPHOS activity, which was counteracted by overexpression of <em>LINC00667</em>. Cycloheximide (CHX) chase experiments revealed that <em>LINC00667</em> overexpression accelerated POTEE degradation, while treatment with the proteasome inhibitor MG132 stabilized POTEE levels. Furthermore, we identified TRIM33 as the E3 ligase responsible for mediating POTEE ubiquitination. Collectively, our findings demonstrate that <em>LINC00667</em> inhibits breast cancer progression by promoting TRIM33-mediated ubiquitination and subsequent degradation of POTEE, thereby regulating mitochondrial OXPHOS activity. These results highlight the critical role of <em>LINC00667</em> in the posttranslational regulation of protein stability and mitochondrial function in BC, and suggest that targeting the <em>LINC00667</em>-POTEE axis may represent a potential therapeutic strategy for this disease.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112074"},"PeriodicalIF":3.7000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"LncRNA LINC00667 inhibits breast cancer progression by regulating POTEE to suppress mitochondrial oxidative phosphorylation.\",\"authors\":\"Zhengling Yu , Keying Xu , Yini Shang , Changhui Geng , Youxue Zhang , Lihong Wang\",\"doi\":\"10.1016/j.cellsig.2025.112074\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Breast cancer (BC) is characterized by significant heterogeneity, which is reflected in genetic mutations and aberrant protein expression. Although long noncoding RNAs (lncRNAs) are known to influence the progression of BC, their regulatory roles in posttranslational modifications remain poorly understood. In this study, we investigated the function of <em>LINC00667</em>, an intergenic lncRNA that is downregulated in BC cell lines and tissues. Our results demonstrate that <em>LINC00667</em> serves as a favorable prognostic marker for breast cancer. Functional characterization revealed that overexpression of <em>LINC00667</em> suppresses malignant progression, while its knockdown promotes oncogenic phenotypes in BC. Mechanistically, we used CHIRP and RIP assays to confirm direct binding interactions between <em>LINC00667</em> and two proteins: ubiquitin B (UBB) and POTE ankyrin domain family member E (POTEE). We found that <em>LINC00667</em> reduces POTEE expression and inhibits mitochondrial oxidative phosphorylation (OXPHOS). Specifically, silencing of POTEE decreased the expression of OXPHOS complexes, an effect that could be rescued by knockdown of <em>LINC00667</em>. Conversely, overexpression of POTEE enhanced OXPHOS activity, which was counteracted by overexpression of <em>LINC00667</em>. Cycloheximide (CHX) chase experiments revealed that <em>LINC00667</em> overexpression accelerated POTEE degradation, while treatment with the proteasome inhibitor MG132 stabilized POTEE levels. Furthermore, we identified TRIM33 as the E3 ligase responsible for mediating POTEE ubiquitination. Collectively, our findings demonstrate that <em>LINC00667</em> inhibits breast cancer progression by promoting TRIM33-mediated ubiquitination and subsequent degradation of POTEE, thereby regulating mitochondrial OXPHOS activity. These results highlight the critical role of <em>LINC00667</em> in the posttranslational regulation of protein stability and mitochondrial function in BC, and suggest that targeting the <em>LINC00667</em>-POTEE axis may represent a potential therapeutic strategy for this disease.</div></div>\",\"PeriodicalId\":9902,\"journal\":{\"name\":\"Cellular signalling\",\"volume\":\"135 \",\"pages\":\"Article 112074\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-08-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cellular signalling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0898656825004899\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular signalling","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0898656825004899","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
LncRNA LINC00667 inhibits breast cancer progression by regulating POTEE to suppress mitochondrial oxidative phosphorylation.
Breast cancer (BC) is characterized by significant heterogeneity, which is reflected in genetic mutations and aberrant protein expression. Although long noncoding RNAs (lncRNAs) are known to influence the progression of BC, their regulatory roles in posttranslational modifications remain poorly understood. In this study, we investigated the function of LINC00667, an intergenic lncRNA that is downregulated in BC cell lines and tissues. Our results demonstrate that LINC00667 serves as a favorable prognostic marker for breast cancer. Functional characterization revealed that overexpression of LINC00667 suppresses malignant progression, while its knockdown promotes oncogenic phenotypes in BC. Mechanistically, we used CHIRP and RIP assays to confirm direct binding interactions between LINC00667 and two proteins: ubiquitin B (UBB) and POTE ankyrin domain family member E (POTEE). We found that LINC00667 reduces POTEE expression and inhibits mitochondrial oxidative phosphorylation (OXPHOS). Specifically, silencing of POTEE decreased the expression of OXPHOS complexes, an effect that could be rescued by knockdown of LINC00667. Conversely, overexpression of POTEE enhanced OXPHOS activity, which was counteracted by overexpression of LINC00667. Cycloheximide (CHX) chase experiments revealed that LINC00667 overexpression accelerated POTEE degradation, while treatment with the proteasome inhibitor MG132 stabilized POTEE levels. Furthermore, we identified TRIM33 as the E3 ligase responsible for mediating POTEE ubiquitination. Collectively, our findings demonstrate that LINC00667 inhibits breast cancer progression by promoting TRIM33-mediated ubiquitination and subsequent degradation of POTEE, thereby regulating mitochondrial OXPHOS activity. These results highlight the critical role of LINC00667 in the posttranslational regulation of protein stability and mitochondrial function in BC, and suggest that targeting the LINC00667-POTEE axis may represent a potential therapeutic strategy for this disease.
期刊介绍:
Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo.
Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.