Lingqing Luo, Lingying Kong, Chaoqiang Zheng, Shan Jiang, Zhaolei Cui
Acetyl-CoA acyltransferase 2 (ACAA2), a critical enzyme in fatty acid β-oxidation, has been implicated in various malignancies. However, its impact on renal cell carcinoma (RCC) remains uncertain. This research explores ACAA2's function in RCC. ACAA2's prognostic significance and clinicopathological relevance in RCC were determined using Kaplan-Meier and Cox regression analyses. The effect of ACAA2 on proliferation, migration, invasiveness, and apoptosis was evaluated in vitro. Additionally, the formation of autophagy-related proteins and lipid droplets was analyzed through cellular immunofluorescence, and autophagosomes were observed using transmission electron microscopy (TEM). Low levels of ACAA2 mRNA expression in two RCC subtypes were associated with poor prognosis, identifying ACAA2 as an independent prognostic factor in RCC. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated a significant association between ACAA2 and fatty acid (FA) metabolism, apoptosis, and cellular autophagy. Enhanced expression of ACAA2 significantly reduced the proliferation, migration, and invasion of Caki-1 and Caki-2 cells, while promoting programmed cell death and the degradation of autophagic p62 protein. This enhancement facilitated the conversion of LC3I to LC3II, improving early-stage autophagy and autophagosome formation. Our data further indicate that ACAA2 is associated with the regulation of FA metabolism, as evidenced by reduced free fatty acid (FFA) accumulation, which may impact RCC cell growth. Exogenously added FFAs reduced the suppressive effects of ACAA2 on cancer cell proliferation. Collectively, ACAA2 functions as a tumor suppressor in RCC and may be a predictive biomarker for the disease. The effects of ACAA2 on cell migration, invasion, and proliferation are correlated with the activation of autophagy-related signaling pathways and alterations in lipid metabolism in RCC.