CYP27A1 loss dysregulates cholesterol homeostasis in prostate cancer

Mahmoud A. Alfaqih, Erik R. Nelson, Wen Liu, Rachid Safi, Jeffery S. Jasper, Everardo Macias, Joseph Geradts, J. Will Thompson, Laura G. Dubois, Michael R. Freeman, Ching Yi Chang, Jen Tsan Chi, Donald P. McDonnell, Stephen J. Freedland

Research output: Contribution to journalArticle

Abstract

In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis.

Original languageEnglish (US)
Pages (from-to)1662-1673
Number of pages12
JournalCancer Research
Volume77
Issue number7
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Alfaqih, M. A., Nelson, E. R., Liu, W., Safi, R., Jasper, J. S., Macias, E., Geradts, J., Thompson, J. W., Dubois, L. G., Freeman, M. R., Chang, C. Y., Chi, J. T., McDonnell, D. P., & Freedland, S. J. (2017). CYP27A1 loss dysregulates cholesterol homeostasis in prostate cancer. Cancer Research, 77(7), 1662-1673. https://doi.org/10.1158/0008-5472.CAN-16-2738