Abstract:

Objective

To explore the prognostic and therapeutic significance of cholesterol biosynthesis-related genes （CBRG） in prostate cancer （PCa）.

Methods

The differential expression of cholesterol biosynthesis-related genes in PCa and normal tissues was analyzed using the TCGA database.A risk score prognostic model was constructed through LASSO and multivariate Cox regression analysis.The independent prognostic value of the model for PCa was further validated using univariate and multivariate Cox regression analyses.PCa patients were divided into high-risk and low-risk groups based on the median value of the risk score.GSEA analysis was used to observe the differentially enriched pathways between the high-risk and low-risk groups.The CIBERSORT algorithm was employed to assess tumor immune cell infiltration in the high-risk and low-risk groups.Potential drugs associated with the risk score were screened using the GDSC database，and the correlation between the risk score and the half-maximal inhibitory concentration （IC50） of the drugs was analyzed using the Spearman test.Kaplan-Meier analysis compared the disease-free survival （DFS） of patients with high and low expression of characteristic genes.The Wilcoxon test was used to analyze the expression differences of characteristic genes in enzalutamideresistant versus non-resistant cases.

Results

A prognostic model was constructed that included the genes PMVK，ACSL3，ABCG1，HMGCS2，and CYP11A1.This model had areas under the curve （AUC） of 0.74，0.76，and 0.72 for predicting 1-year，3-year，and 5-year DFS，respectively，with AUCs of 0.70 and 0.69 in the validation dataset for 3-year and 5-year DFS，respectively.Clinical independence analysis revealed that this prognostic model has the ability to independently predict DFS in PCa patients，outperforming other clinical pathological features.Further analysis of tumor immune cell infiltration levels in high-risk and lowrisk groups of PCa patients showed that the infiltration levels of CD8⁺ T cells，follicular helper T cells，and activated NK cells were significantly reduced in the high-risk group，while the infiltration levels of naïve B cells，resting CD4⁺ memory T cells，regulatory T cells，and neutrophils were significantly increased.Drug sensitivity analysis found that the resistance to six drugs，including enzalutamide and lapatinib，was positively correlated with the risk score.GSEA analysis indicated that the high-risk group was primarily enriched in pathways related to oxidative phosphorylation，ribosomes，and proteasomes.Additionally，survival analysis revealed a significant correlation between the expression of the HMGCS2 gene and patients' DFS，indicating a positive effect on tumor prognosis，and it was significantly downregulated in enzalutamide-resistant patients.

Conclusion

Cholesterol biosynthesis-related characteristic genes are independent prognostic markers for prostate cancer，and the HMGCS2 gene may serve as a potential therapeutic target，providing new insights for precision treatment of prostate cancer.

Key words: Prostate cancer, Cholesterol, Biosynthesis, HMGCS, Prognosis, Therapy