ACSL3 通过脂质代谢重编程和 YES1/YAP 轴调控乳腺癌的进展。

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Shirong Tan, Xiangyu Sun, Haoran Dong, Mozhi Wang, Litong Yao, Mengshen Wang, Ling Xu, Yingying Xu
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引用次数: 0

摘要

目的:线粒体脂肪酸氧化是一种代谢途径,其失调被认为是各种癌症的关键因素,因为它能维持癌细胞的存活、增殖和转移。已知酰基-CoA长链合成酶(ACSL)家族可激活长链脂肪酸,但ACSL3在乳腺癌中的具体作用尚未确定:方法:我们利用肿瘤样本数据评估了 ACSL3 在乳腺癌中的预后价值。方法:我们利用肿瘤样本数据评估了ACSL3在乳腺癌中的预后价值,并进行了功能增益和功能缺失试验,以确定ACSL3在体外和体内的作用及下游调控机制:结果:与正常组织相比,ACSL3在乳腺癌组织中的表达明显下调,这种表型与生存率的提高相关。功能实验显示,乳腺癌细胞中的 ACSL3 基因敲除可促进细胞增殖、迁移和上皮-间质转化。从机理上讲,ACSL3 可抑制 β 氧化和相关副产物的形成,从而抑制乳腺癌的恶性行为。重要的是,研究发现 ACSL3 与酪氨酸激酶 Src 家族成员 YES 原癌基因 1 相互作用,并通过 Tyr419 处的磷酸化抑制其活化。活化的YES1减少,从而抑制了YAP1的核共定位和转录复合物的形成,并抑制了其下游基因在乳腺癌细胞核中的表达:ACSL3通过阻碍脂质代谢重编程,并通过磷酸化YES1介导的YAP1及其下游通路抑制恶性行为,从而抑制乳腺癌的进展。这些研究结果表明,ACSL3 可作为潜在的生物标志物和乳腺癌综合治疗策略的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis.

Objective: Mitochondrial fatty acid oxidation is a metabolic pathway whose dysregulation is recognized as a critical factor in various cancers, because it sustains cancer cell survival, proliferation, and metastasis. The acyl-CoA synthetase long-chain (ACSL) family is known to activate long-chain fatty acids, yet the specific role of ACSL3 in breast cancer has not been determined.

Methods: We assessed the prognostic value of ACSL3 in breast cancer by using data from tumor samples. Gain-of-function and loss-of-function assays were also conducted to determine the roles and downstream regulatory mechanisms of ACSL3 in vitro and in vivo.

Results: ACSL3 expression was notably downregulated in breast cancer tissues compared with normal tissues, and this phenotype correlated with improved survival outcomes. Functional experiments revealed that ACSL3 knockdown in breast cancer cells promoted cell proliferation, migration, and epithelial-mesenchymal transition. Mechanistically, ACSL3 was found to inhibit β-oxidation and the formation of associated byproducts, thereby suppressing malignant behavior in breast cancer. Importantly, ACSL3 was found to interact with YES proto-oncogene 1, a member of the Src family of tyrosine kinases, and to suppress its activation through phosphorylation at Tyr419. The decrease in activated YES1 consequently inhibited YAP1 nuclear colocalization and transcriptional complex formation, and the expression of its downstream genes in breast cancer cell nuclei.

Conclusions: ACSL3 suppresses breast cancer progression by impeding lipid metabolism reprogramming, and inhibiting malignant behaviors through phospho-YES1 mediated inhibition of YAP1 and its downstream pathways. These findings suggest that ACSL3 may serve as a potential biomarker and target for comprehensive therapeutic strategies for breast cancer.

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来源期刊
Cancer Biology & Medicine
Cancer Biology & Medicine Medicine-Oncology
CiteScore
9.80
自引率
3.60%
发文量
1143
审稿时长
12 weeks
期刊介绍: Cancer Biology & Medicine (ISSN 2095-3941) is a peer-reviewed open-access journal of Chinese Anti-cancer Association (CACA), which is the leading professional society of oncology in China. The journal quarterly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China.
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