Intratumoral sterol-27-hydroxylase (CYP27A1) expression in relation to cholesterol synthesis and vitamin D signaling and its association with lethal prostate cancer

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    • Nabeela A Khan
    • Konrad Stopsack
    • Emma H Allott
    • Travis Gerke
    • Edward L Giovannucci
    • Lorelei A Mucci
    • Philip W Kantoff

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    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 = 132) and intratumoral vitamin D receptor protein expression (VDR, n = 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 odds ratio for lowest vs. highest quartile of CYP27A1, 2.64; 95% CI, 1.24-5.62). This association was attenuated when additionally adjusting for Gleason grade (odds ratio, 1.76; 95% CI, 0.75-4.17).

    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.

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    • Intratumoral sterol-27-hydroxylase (CYP27A1) expression in relation to cholesterol synthesis and vitamin D signaling and its association with lethal prostate cancer

      Rights statement: Copyright 2019 AACS. This work is made available online in accordance with the publisher’s policies. Please refer to any applicable terms of use of the publisher.

      Accepted author manuscript, 209 KB, PDF-document

      Embargo ends: 13/03/2020

    DOI

    Original languageEnglish
    JournalCancer Epidemiology Biomarkers & Prevention
    Journal publication date13 Mar 2019
    Early online date13 Mar 2019
    DOIs
    Publication statusEarly online date - 13 Mar 2019

    ID: 166438478