SAT-314 Elevated Expression Of Squalene Epoxidase Gene (sqle) Promotes Prostate Cancer Aggressiveness By Altering Lipid Metabolism

Abstract Disclosure: C. Springer: None. T. Janas: None. K.H. Stopsack: None. D.R. Schmidt: None. D. Ma: None. Z. Li: None. M.G. Vander Heiden: None. K.L. Penny: None. P.A. Scheet: None. T.L. Lotan: None. A. Amon: None. L.A. Mucci: None. X. Su: None. Prostate cancer (PCa) remains the second leading cause of cancer-related mortality among men in the United States. Aneuploidy, characterized by imbalanced chromosome numbers, correlates with lethal PCa progression. Chromosome 8q (chr8q) gain is one of the most frequent aneuploidy events, occurring in 23% of PCa cases. Recently, we ranked odds ratio (OR) for each chr8q gene to assess the long-term risk of metastases and death from PCa (lethal disease) within 403 patients in the HPFS and PHS cohorts. We observed that the squalene monooxygenase (SQLE) is one of the top ranked genes on chr8q, with an OR of 2.2. SQLE, encoding the key enzyme in cholesterol biosynthesis pathway, has been shown to be associated with poor prognosis in PCa, suggesting it as a potential target to treat aggressive PCa. Datasets such as The Cancer Genome Atlas (TCGA) and the Prostate Cancer Atlas were used to correlate the copy number and mRNA expression levels and the progression of PCa. We focused on mouse prostate organoids (both normal and cancer-like) and human metastatic prostate cell line, VCaP cell, expressing TMPRSS2-ERG gene, which approximately 50% of PCa cases harbors. We used lentiviral transduction to introduce either SQLE overexpression in prostate organoids (which harbor euploid SQLE) or SQLE shRNA in VCaP cells (which harbor increased SQLE). Molecular and cellular approaches were employed to study the influences of altered SQLE levels on target prostate cells. Ultra performance liquid chromatography (UPLC) with mass spectrometry (MS) was used to analyze the changed levels of squalene and lipid profiles when SQLE levels were altered. Overexpression of SQLE in cancer-like mouse prostate organoid models led to increased invasive structures and proliferation. RNA sequencing data suggested that alteration in SQLE levels changes gene signatures related to lipid metabolisms. Interestingly, SQLE overexpression decreased TMPRSS2-ERG protein levels in the organoids. In contrast, SQLE knockdown in VCaP cells resulted in significantly increased TMPRSS2-ERG protein levels. ERG is associated with fatty acid metabolism in PCa cohorts. Our findings suggest that aneuploidy-associated overexpression of SQLE drives PCa aggressiveness by modulating lipid metabolism, particularly through its impact on cholesterol biosynthesis and TMPRSS2-ERG regulation. Targeting SQLE could present a novel therapeutic approach to treat aggressive PCa. Presentation: Saturday, July 12, 2025