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

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. 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. 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. 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.