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ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis.

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Title: ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis.
Authors: Tan S; Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110000, China., Sun X; Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110000, China., Dong H; Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110000, China., Wang M; Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110000, China., Yao L; Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110000, China., Wang M; Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China., Xu L; Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110000, China., Xu Y; Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110000, China.
Source: Cancer biology & medicine [Cancer Biol Med] 2024 Jul 01; Vol. 21 (7).
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Chinese Anti-Cancer Association Country of Publication: China NLM ID: 101588850 Publication Model: Print Cited Medium: Internet ISSN: 2095-3941 (Print) Linking ISSN: 20953941 NLM ISO Abbreviation: Cancer Biol Med Subsets: MEDLINE
Imprint Name(s): Original Publication: [Tianjin] : Chinese Anti-Cancer Association
MeSH Terms: Breast Neoplasms*/pathology , Breast Neoplasms*/metabolism , Breast Neoplasms*/genetics , Coenzyme A Ligases*/metabolism , Coenzyme A Ligases*/genetics , YAP-Signaling Proteins*/metabolism , Transcription Factors*/metabolism , Transcription Factors*/genetics , Proto-Oncogene Proteins c-yes*/metabolism , Proto-Oncogene Proteins c-yes*/genetics , Lipid Metabolism* , Disease Progression* , Cell Proliferation* , Proto-Oncogene Mas*, Adaptor Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Humans ; Female ; Animals ; Mice ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Epithelial-Mesenchymal Transition ; Mice, Nude ; Prognosis ; Cell Movement ; Signal Transduction ; Metabolic Reprogramming ; Long-Chain-Fatty-Acid-CoA Ligase
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.
(Copyright: © 2024, The Authors.)
Competing Interests: No potential conflicts of interest are disclosed.
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Grant Information: 82203786 National Natural Science Foundation of China; 2022-YGJC-68 Natural Science Foundation of Liaoning Province of China; 2023-BS-105 Natural Science Foundation of Liaoning Province of China; CYBER-2021-A02 Chinese Young Breast Experts Research Project; CYBER-2022-001 Chinese Young Breast Experts Research Project
Contributed Indexing: Keywords: ACSL3; Breast cancer; YAP; lipid metabolism; metastasis
Substance Nomenclature: EC 6.2.1.- (Coenzyme A Ligases)
0 (YAP-Signaling Proteins)
EC 6.2.1.3 (Long-Chain-Fatty-Acid-CoA Ligase)
0 (YAP1 protein, human)
0 (MAS1 protein, human)
0 (Transcription Factors)
0 (Proto-Oncogene Mas)
EC 2.7.10.2 (Proto-Oncogene Proteins c-yes)
EC 2.7.10.2 (YES1 protein, human)
0 (Adaptor Proteins, Signal Transducing)
Entry Date(s): Date Created: 20240702 Date Completed: 20240725 Latest Revision: 20250103
Update Code: 20260130
PubMed Central ID: PMC11271223
DOI: 10.20892/j.issn.2095-3941.2023.0309
PMID: 38953696
Database: MEDLINE
Description
ISSN:2095-3941
DOI:10.20892/j.issn.2095-3941.2023.0309