Intratumoral Sterol-27-Hydroxylase (CYP27A1) Expression in Relation to Cholesterol Synthesis and Vitamin D Signaling and Its Association with Lethal Prostate Cancer

Abstract

Background: Higher intratumoral cholesterol synthesis is associated with a worse prognosis in prostate cancer. The vitamin D-regulated enzyme sterol-27-hydroxylase (CYP27A1) converts cholesterol to 27-hydroxycholesterol, potentially lowering intracellular cholesterol levels. We hypothesized that low CYP27A1 expression is associated with high cholesterol synthesis, low vitamin D signaling, and higher risk of lethal prostate cancer.Methods: In 404 patients from the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS), we assessed intratumoral CYP27A1 expression and proxies of cholesterol synthesis using transcriptome profiling, prediagnostic plasma 25-hydroxyvitamin D [25(OH)D; n ¼ 132], and intratumoral vitamin D receptor protein expression (VDR; n ¼ 300). Patients were followed for metastases and prostate cancer mortality (lethal cancer; median follow-up, 15.3 years).Results: CYP27A1 expression was lower in tumors with higher Gleason grade and higher expression of cholesterol synthesis enzymes, including the second rate-limiting enzyme, SQLE. We did not detect consistent associations between CYP27A1 and 25(OH)D, VDR, or CYP24A1 mRNA expression. Lower CYP27A1 was associated with higher risk of lethal cancer in both cohorts, independent of SQLE [adjusted OR for lowest vs. highest quartile of CYP27A1, 2.64; 95% confidence interval (CI), 1.24-5.62]. This association was attenuated when additionally adjusting for Gleason grade (OR, 1.76; 95% CI,.Conclusions: Low CYP27A1 expression was associated with higher cholesterol synthesis and a higher risk of lethal disease.Impact: These observations further support the hypothesis that intratumoral cholesterol accumulation through higher synthesis and decreased catabolism is a feature of lethal prostate cancer. a On the basis of IHC for ERG protein. Missing for 39 patients in total.Khan, Stopsack et al.

Peer Review #1 of "Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis (v0.1)"

“…Recent research indicated that vitamin D inhibits cell proliferation and maintains the stem cell phenotype by increasing several stemness-related gene expressions (Fernández-Barral et al 2020). Besides, one of the main vitamin Drelated genes, CYP24A1 was found to be negatively associated with the prognosis of prostate cancer (Khan et al 2019). Therefore, vitamin D-related genes are critical in the development and progression of carcinogenesis.…”

Role of 27-hydroxycholesterol and its metabolism in cancer progression: Human studies

“…In fact, if an enhancing effect of 27OHC on primary breast cancer is dependent upon its binding to estrogen receptors, the oxysterol exerted promotion of lung metastases seems to not involve ER [15]. Besides the epidemiological studies to date available that suggest a significant correlation between high 27OHC levels and reduced risk of breast cancer [20,21], one should consider that all reports related to human prostate cancer consistently indicate a protective and not a detrimental role of 27OHC as to tumor progression and growth [26][27][28][29][30].…”

“…Expression of CYP27A1 was again found lower in advanced stage carcinomas, with high Gleason score. Importantly, the clinical cases from both cohorts with higher risk of developing metastasis and eventually death were consistently showing a relatively low expression of the 27OHC synthetic enzyme in the neoplastic tissue [29].…”

Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis

“…Recent research indicated that vitamin D inhibits cell proliferation and maintains the stem cell phenotype by increasing several stemness-related gene expressions ( Fernández-Barral et al, 2020 ). Besides, one of the main vitamin D-related genes, CYP24A1 was found to be negatively associated with the prognosis of prostate cancer ( Khan et al, 2019 ). Therefore, vitamin D-related genes are critical in the development and progression of carcinogenesis.…”