Background 3-oxoacyl-ACP synthase (OXSM) is a key enzyme in the mitochondrial fatty acid synthesis pathway, playing a role in the biosynthesis of lipoic acid as well as long-chain fatty acids required for mitochondrial function. Recent studies have shown that OXSM is involved in the progression of various tumors, but its role in colon cancer tumorigenesis remains to be investigated. The aim of this study is to investigate the function and underlying mechanism of OXSM in colon cancer.

Methods Tissue microarrays and immunohistochemistry are used to analyze OXSM expression and its correlation with clinicopathological parameters. The upstream microRNA is identified by SmallRNA-seq and bioinformatics analyses. Cell growth and cell migration are measured in HCT116 cells simultaneously depleted of microRNA and OXSM. The RNA-seq is adopted to determine the signaling pathway of OXSM. The mouse xenograft assay is studied to confirm the role of OXSM in vivo.

Results In this study, we find that OXSM level is significantly low in colon cancer patients, and low OXSM expression correlates with poor patient survival in colon cancer. The SmallRNA-seq analysis and biofunctional tests reveal that miR-4659a-3p is a novel microRNA of OXSM. Depletion of OXSM leads to the promotion of cell proliferation and migration in colon cancer, while simultaneously downregulation of miR-4659a-3p rescues the promotive phenomenon in cells ablated with OXSM. RNA-seq result shows that OXSM mediated the regulation of cytokine and chemokine biosynthesis and metabolism, including EGR1, HMOX1, ZFP36, TLR3, IL1RAP, TLR1, IFIH1, P2RX7. Moreover, OXSM depletion nude mice exhibit decreased level of cytokine and chemokine in tumor tissues and are more prone to tumorigenesis.

Conclusions miR-4659a-3p promotes the formation of colon cancer by inhibiting cytokine and chemokine biosynthesis and metabolism via OXSM, providing a potential target for colon cancer diagnosis and therapy.