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27-hydroxycholesterol and DNA damage repair: implication in prostate cancer
Gloria Cecilia Galvan1, Nadine A Friedrich1, Sanjay Das1,2,3
1Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Frontiers in Oncology
|January 8, 2024
Summary
27-hydroxycholesterol (27HC) induces DNA damage and "BRCAness" in prostate cancer (PC) cells, suggesting potential sensitivity to PARP inhibitors. Restoring the CYP27A1/27HC axis may offer a novel therapeutic strategy for PC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cholesterol homeostasis is altered in prostate cancer (PC).
- The enzyme CYP27A1 converts cholesterol to 27-hydroxycholesterol (27HC), and its loss is frequent in PC.
- Restoring the CYP27A1/27HC axis has previously shown to inhibit PC growth.
Purpose of the Study:
- To investigate the underlying mechanism of 27HC-mediated anti-prostate cancer effects.
- To explore the impact of 27HC on DNA damage repair pathways in PC cells.
- To assess the correlation between CYP27A1 expression and DNA repair gene signatures in human PC datasets.
Main Methods:
- In vitro treatment of LNCaP (AR+) and DU145 (AR-) PC cells with 27HC.
- Transcriptome profiling using microarrays and gene set enrichment analysis.
- Validation of key gene changes at mRNA and protein levels, comet assays for DNA damage, and analysis of human PC transcriptomes.
Main Results:
- 27HC downregulated DNA damage repair pathways and induced "BRCAness" in LNCaP cells.
- Higher CYP27A1 expression correlated with decreased DNA repair gene signatures in castration-sensitive PC (CSPC).
- 27HC increased DNA damage in LNCaP cells, with additive effects when combined with olaparib (a PARP inhibitor).
Conclusions:
- 27HC induces "BRCAness" and DNA damage, potentially increasing sensitivity to PARP inhibitors in CSPC.
- The CYP27A1/27HC axis represents a potential therapeutic target for prostate cancer.
- Further research is warranted to explore 27HC's role in synthetic lethality strategies for PC treatment.
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