Squalene synthase induces ERα expression via cholesterol supplementation to confer statin resistance in lung cancer cells

BACKGROUND: Sterol regulatory element-binding proteins (SREBPs) are master regulators of cholesterol and lipid biosynthesis - pathways increasingly linked to cancer progression. Statins, which inhibit HMG-CoA reductase to lower cholesterol, have shown potential in reducing cancer recurrence. However, their efficacy in lung cancer remains uncertain, and predictive biomarkers for statin responsiveness are still lacking. METHODS: We examined the relationship between cholesterol biosynthesis and estrogen receptor alpha (ERα) signaling and assessed the therapeutic potential of targeting this axis in lung cancer models. RESULTS: Overexpression of farnesyl-diphosphate farnesyltransferase 1 (FDFT1), also known as squalene synthase (SQS), significantly increased the IC50 of lovastatin in lung cancer cell lines, indicating a role in mediating statin resistance. Gene expression profiling revealed enrichment of estrogen receptor alpha (ERα) signaling in SQS-overexpressing cells. Immunohistochemical analysis of 125 NSCLC patient samples showed a positive correlation between SQS and ERα protein expression, and their co-expression was significantly associated with poorer disease-free survival. Mechanistically, SQS upregulated ERα at the protein level via cholesterol replenishment, without altering ESR1 mRNA levels, suggesting a post-transcriptional regulatory mechanism. CONCLUSION: SQS promotes statin resistance in lung cancer by stabilizing ERα through cholesterol replenishment. Its co-expression with ERα predicts poor prognosis, highlighting the SQS–ERα axis as a potential therapeutic target and biomarker for stratifying patients likely to benefit from statin–antiestrogen combination therapy.