CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer

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 tra...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-04, Vol.77 (7), p.1662-1673
Main Authors: Alfaqih, Mahmoud A, Nelson, Erik R, Liu, Wen, Safi, Rachid, Jasper, Jeffery S, Macias, Everardo, Geradts, Joseph, Thompson, J Will, Dubois, Laura G, Freeman, Michael R, Chang, Ching-Yi, Chi, Jen-Tsan, McDonnell, Donald P, Freedland, Stephen J
Format: Article
Language:English
Subjects:
Animals
Bioinformatics
Cell Line, Tumor
Cell lines
Cholestanetriol 26-Monooxygenase - genetics
Cholesterol
Cholesterol - metabolism
Computational Biology
DNA microarrays
Gene Expression Regulation, Enzymologic
Genes
Homeostasis
Humans
Hydroxycholesterols - pharmacology
Male
Mice
Pathogenesis
Prostate
Prostate cancer
Prostatic Neoplasms - etiology
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Receptor density
Receptors, LDL - genetics
Sterol Regulatory Element Binding Protein 2 - antagonists & inhibitors
Transcription
Tumor cell lines
Xenografts
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Summary: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 and in tumor xenografts. Studies performed 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. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-16-2738