Pharmacologic inhibition of SREBP-driven lipogenesis suppresses metastatic progression in prostate cancer

Prostate cancer (PCa) progression is increasingly recognized as a metabolically driven process, particularly through alterations in lipid metabolism. Sterol regulatory element-binding proteins (SREBPs) are master transcription factors that regulate genes involved in lipogenesis and are often upregulated in advanced prostate cancer, leading to aberrant lipid accumulation, and are associated with poor prognosis and disease progression. Despite advances in characterizing the metabolic phenotype of PCa, a critical gap remains in understanding how SREBP-driven lipid remodeling mechanistically contributes to the metastatic dissemination of PCa. Our analysis of publicly available patient datasets revealed increased gene expression of SREBPs in prostate tumors compared to normal prostate tissue. Furthermore, we observed substantially higher SREBP gene expression in metastatic samples compared to primary tumors. We also found notably higher levels of SREBPs in the more invasive PC3M and C4-2B cell lines than in their less invasive counterparts, PC3 and LNCaP. Based on these findings, we hypothesize that inhibition of SREBPs by fatostatin could be an effective therapeutic strategy against lethal metastatic prostate cancer. We found that fatostatin inhibited the viability, proliferation, clonogenic survival, migration, and invasion of the more invasive PCa cell lines, with significantly greater potency than in less invasive lines. Immunoblotting confirmed that fatostatin inhibited both SREBPs and their downstream targets more effectively in more invasive PCa cell lines than in less invasive ones. We then performed RNA-Seq and pathway analysis on all cell lines treated with fatostatin. We found that pathways related to EMT and mTORC1 are significantly downregulated in the more invasive prostate cancer cell lines compared to their less invasive counterparts. Overall, our results demonstrate that SREBP-driven lipid metabolism mechanistically contributes to PCa invasiveness and pharmacological inhibition of SREBPs may improve outcomes in lethal metastatic prostate cancer.