CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer

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 (SREBP2) and downregulating low-density lipoprotein receptor (LDLR) 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.

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

“…In breast cancer, several studies found CYP27A1 expression to be higher in high-grade compared with low-grade cancers (7,8). In prostate cancer, a relatively strong, inverse relationship with Gleason grade has been reported previously (11) and was confirmed by our data. CYP27A1 expression has also been reported to be lower in castration-resistant cancer tissue compared with tissue from castration-sensitive tumors (28).…”

“…These observations suggest that in tumors with activated cholesterol synthesis, hydroxylation of cholesterol to 27-hydroxycholesterol is inhibited, perhaps giving these rapidly dividing cells a selective advantage when more cholesterol is available, for example, cell membrane formation. Concordantly, a preclinical study found the addition of 27-hydroxycholesterol to prostate cancer cell lines and xenografts attenuated their growth and decreased the expression of SREBP2, the main transcription factor regulating cholesterol synthesis (11). However, discordant experimental results, partially using the same cell line, have been reported as well (22).…”

“…CYP27A1 also catalyzes the 25-hydroxylation step of vitamin D, which might have a protective effect in various cancers including prostate cancer (9,10). In prostate cancer, a recent study reported CYP27A1 expression to be strongly inversely related to Gleason grade (11), but the association with long-term clinical outcomes is unknown.…”

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

“…However, in contrast to the above findings, 27HC inhibited prostate cancer cell invasion [83]. Furthermore, adopting a bioinformatics approach, Alfaqih et al found CYP27A1 is dramatically downgraded in prostate cancer [84]. More importantly, low expression of the enzyme is associated with decreased progression free survival as well as higher tumor grade, suggesting 27HC might actually be beneficial.…”

“…Overexpression of CYP27A1 led to slower tumor growth of 22RV1 xenografts. The growth-inhibitory effects were attributed to the ability of 27HC to inhibit sterol regulatory-element binding protein 2 (SREBP2) [84]. Regardless, more work investigating the impact of 27HC on prostate cancer progression will be required to resolve the results of these conflicting studies.…”