Abstract：
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.
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.
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。因为它维持癌细胞的存活，扩散,和转移。已知酰基辅酶A合成酶长链（ACSL）家族可激活长链脂肪酸，然而ACSL3在乳腺癌中的具体作用尚未确定.
方法：我们使用来自肿瘤样本的数据评估ACSL3在乳腺癌中的预后价值。还进行了功能增益和功能丧失测定以确定ACSL3在体外和体内的作用和下游调节机制。
结果：与正常组织相比，ACSL3在乳腺癌组织中的表达明显下调，该表型与生存结局改善相关。功能实验表明，ACSL3敲低在乳腺癌细胞中促进细胞增殖，迁移,和上皮-间质转化。机械上,ACSL3被发现抑制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,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的磷酸化抑制其激活。激活的YES1的减少因此抑制了YAP1核共定位和转录复合物的形成，及其下游基因在乳腺癌细胞核中的表达。
结论：ACSL3通过阻止脂质代谢重编程抑制乳腺癌进展，并通过磷酸化YES1介导的YAP1及其下游通路抑制恶性行为。这些结果表明，ACSL3可能是乳腺癌综合治疗策略的潜在生物标志物和靶标。
方法：我们使用来自肿瘤样本的数据评估ACSL3在乳腺癌中的预后价值。还进行了功能增益和功能丧失测定以确定ACSL3在体外和体内的作用和下游调节机制。
结果：与正常组织相比，ACSL3在乳腺癌组织中的表达明显下调，该表型与生存结局改善相关。功能实验表明，ACSL3敲低在乳腺癌细胞中促进细胞增殖，迁移,和上皮-间质转化。机械上,ACSL3被发现抑制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,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的磷酸化抑制其激活。激活的YES1的减少因此抑制了YAP1核共定位和转录复合物的形成，及其下游基因在乳腺癌细胞核中的表达。
结论：ACSL3通过阻止脂质代谢重编程抑制乳腺癌进展，并通过磷酸化YES1介导的YAP1及其下游通路抑制恶性行为。这些结果表明，ACSL3可能是乳腺癌综合治疗策略的潜在生物标志物和靶标。
