Mp20-02 27 hydroxycholesterol and dna damage repair: implications in prostate cancer

You have accessJournal of UrologyCME1 Apr 2023MP20-02 27 HYDROXYCHOLESTEROL AND DNA DAMAGE REPAIR: IMPLICATIONS IN PROSTATE CANCER Cecilia G. Galvan, Nadine A. Friedrich, Sanjay Das, James P. Daniels, Michael R. Freeman, Ryusuke Suzuki, Sergio Sanders, Sara Pollan, Shweta Dambal, and Stephen J. Freedland Cecilia G. GalvanCecilia G. Galvan More articles by this author , Nadine A. FriedrichNadine A. Friedrich More articles by this author , Sanjay DasSanjay Das More articles by this author , James P. DanielsJames P. Daniels More articles by this author , Michael R. FreemanMichael R. Freeman More articles by this author , Ryusuke SuzukiRyusuke Suzuki More articles by this author , Sergio SandersSergio Sanders More articles by this author , Sara PollanSara Pollan More articles by this author , Shweta DambalShweta Dambal More articles by this author , and Stephen J. FreedlandStephen J. Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recent studies from our group have reported that cholesterol homeostasis in prostate cancer (PC) is controlled by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, acts as a cellular cholesterol sensor in prostate cells. Furthermore, the loss of the CYP27A1/27HC axis is correlated with PC pathogenesis. Herein, we sought to better understand the mechanism of 27HC-mediated anti-PC effects. METHODS: LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or control. Transcriptome profiling was done with Affymetrix GeneChip™ microarray assay and key changes validated by qPCR. Differential expression and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Human transcriptome signatures were analyzed from the Prostate Cancer Transcriptome Atlas (PCTA). DNA damage was assessed via comet assays and cell growth using proliferation assays. RESULTS: In a transcriptome analysis, 27HC treatment resulted in downregulation of Hallmark pathways related to DNA damage repair, decreased expression of key cell cycle genes, and induced BRCAness (Figure 1). FEN1 and RAD51 decreased expression were confirmed by qPCR. Using publicly available data, we found a correlation between higher CYP27A1 expression (i.e. higher intracellular 27HC) and decreased DNA repair gene expression among 1,321 human transcriptomes. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in PC cells via neutral comet assay. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with Olaparib, a PARP inhibitor, we showed additive anti-tumor activity. CONCLUSIONS: Our research suggests 27HC treatment, via cholesterol depletion, induces BRCAness and leads to increased DNA damage. This DNA damage when combined with PARP inhibitors leads to additive anti-PC effects and may be a potential effective therapy in PC. Additional studies are needed to directly test whether 27HC creates a synthetic lethality to PARP inhibitors and other DNA damaging agents. Source of Funding: Dr. Galvan is funded by the Department of Defense Health Disparities Research Fellowship. Dr. Das was supported by the Patient Centered Outcomes in Urological and Gynecological Cancers (PCORT UroGynCan). Dr. Daniels was funded by the NIH grants TL1 DK132768 and U2C DK129496. Dr. Friedrich was funded by NIH grant T32 CA240172-03. Other funds: Department of Defense Prostate Cancer Research Program © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e275 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cecilia G. Galvan More articles by this author Nadine A. Friedrich More articles by this author Sanjay Das More articles by this author James P. Daniels More articles by this author Michael R. Freeman More articles by this author Ryusuke Suzuki More articles by this author Sergio Sanders More articles by this author Sara Pollan More articles by this author Shweta Dambal More articles by this author Stephen J. Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...