Acetyl CoA Carboxylase 1 Downregulation Promotes Esophageal Squamous Cell Carcinoma Metastasis by Activating the CXCL8–Neutrophil Extracellular Trap Axis

Esophageal squamous cell carcinoma (ESCC) metastasis remains a major cause of poor prognosis. Acetyl?CoA carboxylase 1 (ACC1), a rate?limiting enzyme in fatty acid synthesis, has been implicated in tumor progression but its role in ESCC is unclear. This study investigated whether and how ACC1 downregulation drives ESCC metastasis.

ACC1 expression was examined in 98 ESCC patient tissues by RT?qPCR and in a 91?sample tissue microarray by immunohistochemistry. ACC1 knockdown and overexpression were established in KYSE?450, KYSE?150 and KYSE?140 cells. Cell migration and invasion were assessed by Transwell assays. RNA?seq, chromatin immunoprecipitation, and dual?luciferase reporter assays were used to identify downstream targets. Neutrophil recruitment and neutrophil extracellular trap (NET) formation were evaluated in vitro using human peripheral blood neutrophils. A tail?vein lung metastasis model in BALB/c nude mice was used for in vivo validation, with or without the PAD4 inhibitor (NET inhibitor).

Low ACC1 expression correlated significantly with lymph node metastasis and shorter overall survival in ESCC patients. ACC1 knockdown did not alter fatty acid levels or proliferation but markedly enhanced ESCC cell migration and invasion. Mechanistically, ACC1 knockdown increased intracellular acetyl?CoA, leading to p300?dependent histone H3 acetylation, which upregulated c?Fos and consequently CXCL8 transcription. CXCL8 activated PI3K/AKT and MEK/ERK signaling via CXCR1/2, induced epithelial?mesenchymal transition, and promoted autocrine migration/invasion. Paracrinally, CXCL8 recruited neutrophils and induced NET formation, further facilitating ESCC cell migration. In vivo, ACC1 knockdown increased lung metastasis, which was suppressed by PAD4 inhibitor treatment. Clinically, high CXCL8 levels and abundant NETs in ESCC tissues were associated with poor prognosis.

ACC1 downregulation promotes ESCC metastasis through a dual autocrine and paracrine mechanism involving the CXCL8–NET axis. Targeting this axis may offer a therapeutic strategy for ESCC patients with low ACC1 expression.

Keywords: Acetyl?CoA carboxylase 1, CXCL8, Esophageal squamous cell carcinoma, Neutrophil extracellular traps.

Jiaping Tang is a PhD student at the School of Medicine, Southeast University, Nanjing, China. She earned her Master’s degree in Physiology from Nankai University in 2022, focusing on tumor immunology. Her current research centers on the metabolic and immune mechanisms of esophageal and pancreatic cancers. She has published several papers in peer-reviewed journals. Her research interests include cancer metastasis, tumor microenvironment, and immunotherapy.