SREBF2 enhances lipid metabolism and represses anti-tumor immune responses in cervical cancer by increasing ACAT2

The enzymes acetyl-CoA acetyltransferase (ACATs) are membrane-bound enzymes that play critical roles in the regulation of cellular cholesterol homeostasis in various tissues. Here, we aim to assess the effect of ACAT2 on lipid accumulation in cervical cancer (CC). ACAT2 expression is enhanced in CC and is closely associated with the immune evasion and clinical progression of CC. Knockdown of ACAT2 expression in CC cells inhibits CC growth, improves survival in tumor-bearing C57BL/6 mice, and enhances anti-tumor immune responses by natural killer and CD8⁺ T cells. Protein expression of sterol regulatory element-binding transcription factor 2 (SREBF2) is elevated in CC and mediates the transcriptional activation of ACAT2. E3 ubiquitin-protein ligase parkin (PRKN) expression is attenuated in CC, which results in a diminished level of ubiquitination of SREBF2 and enhanced stability of SREBF2. PRKN inhibits cholesterol accumulation in CC, activates mitophagy, and ameliorates immune evasion through inhibition of SREBF2/ACAT2. Overexpression of SREBF2 blocks the anti-tumor effects of PRKN in an ACAT2-dependent manner. The present study underscores the pivotal function of ACAT2 in CC progression and delineates its potential as a therapeutic latent strategy. This approach involves the strategic obstruction of the metabolic pathway associated with ACAT2.