LncRNA LINC00667通过调节POTEE抑制线粒体氧化磷酸化抑制乳腺癌进展。

IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Zhengling Yu , Keying Xu , Yini Shang , Changhui Geng , Youxue Zhang , Lihong Wang
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引用次数: 0

摘要

乳腺癌(Breast cancer, BC)具有显著的异质性,这体现在基因突变和蛋白表达异常上。虽然已知长链非编码rna (lncRNAs)影响BC的进展,但它们在翻译后修饰中的调节作用仍然知之甚少。在这项研究中,我们研究了LINC00667的功能,这是一种在BC细胞系和组织中下调的基因间lncRNA。我们的研究结果表明,LINC00667是一个良好的乳腺癌预后标志物。功能表征显示,LINC00667过表达抑制恶性进展,而其敲低促进BC的致癌表型。在机制上,我们使用CHIRP和RIP测定来证实LINC00667与两种蛋白:泛素B (UBB)和POTE锚定结构域家族成员E (POTEE)之间的直接结合相互作用。我们发现LINC00667降低POTEE表达并抑制线粒体氧化磷酸化(OXPHOS)。具体来说,POTEE的沉默降低了OXPHOS复合物的表达,这一效应可以通过敲低LINC00667来挽救。相反,过表达POTEE可增强OXPHOS活性,而过表达LINC00667可抵消这一作用。环己亚胺(CHX)追踪实验表明,LINC00667过表达加速了POTEE的降解,而蛋白酶体抑制剂MG132则稳定了POTEE的水平。此外,我们确定TRIM33是负责介导POTEE泛素化的E3连接酶。总之,我们的研究结果表明,LINC00667通过促进trim33介导的泛素化和随后的POTEE降解,从而调节线粒体OXPHOS活性,从而抑制乳腺癌的进展。这些结果强调了LINC00667在BC蛋白稳定性和线粒体功能的翻译后调控中的关键作用,并提示靶向LINC00667- potee轴可能是该疾病的潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.
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来源期刊
Cellular signalling
Cellular signalling 生物-细胞生物学
CiteScore
8.40
自引率
0.00%
发文量
250
审稿时长
27 days
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.
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