Lipid droplet-associated proteins integrate lipid metabolism, cell cycle, and cytoskeletal remodeling in colon cancer.

Lipid remodeling is a hallmark of colonic tumorigenesis, with lipid droplets emerging as key driver of cellular metabolism and tumor growth. This study investigates how dysregulation of lipid droplet-associated proteins facilitates human colon cancer growth. Using a publicly available, highly selective lipid droplet proteomics dataset, we generated a transcriptomic signature representing 151 lipid droplet-associated proteins (LDs151). This signature was significantly enriched in publicly available human colon cancer transcriptomes, effectively distinguishing tumor from adjacent normal samples. Representative proteins from this signature, including regulators of lipid metabolism, cell cycle, and cytoskeletal organization, were dysregulated in human colonic tumors. Regulators of lipid metabolism, ACSL3, ACSL4, HILPDA, and PNPLA3, had increased protein levels in colon tumors, corresponding to upregulated transcripts, predicting poor patient survival. Protein levels of cell cycle regulators CDC42, PRR11, SFN, and TIP30, as well as cytoskeletal regulators DSP, MICAL2, LASP1, and CFL1, were increased despite unchanged or reduced transcript levels in colonic tumors. Moreover, stimulation of lipid droplet accumulation by oleic acid further increased RNA and protein levels of these regulators in colon cancer cells, HCT116 and HT29, with ACSL3, CDC42, SFN, and TIP30 showing cell line-specific differences in expression. Functional studies demonstrated that silencing ACSL4, PRR11, LASP1, or MICAL2 attenuated proliferation, cell cycle progression, and migration of colon cancer cells stimulated with oleic acid. These findings suggest that lipid droplets may serve as a hub coordinating metabolic, cell cycle, and cytoskeletal pathways that drive colon cancer growth, highlighting lipid droplet-associated proteins as potential biomarkers and therapeutic targets.