27-hydroxycholesterol and DNA damage repair: implication in prostate cancer
IntroductionWe previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In thi...
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| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1251297/full |
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| author | Gloria Cecilia Galvan Nadine A. Friedrich Sanjay Das Sanjay Das Sanjay Das James P. Daniels Sara Pollan Shweta Dambal Ryusuke Suzuki Sergio E. Sanders Sungyong You Hisashi Tanaka Hisashi Tanaka Yeon-Joo Lee Wei Yuan Johann S. de Bono Johann S. de Bono Irina Vasilevskaya Karen E. Knudsen Michael R. Freeman Stephen J. Freedland Stephen J. Freedland |
| author_facet | Gloria Cecilia Galvan Nadine A. Friedrich Sanjay Das Sanjay Das Sanjay Das James P. Daniels Sara Pollan Shweta Dambal Ryusuke Suzuki Sergio E. Sanders Sungyong You Hisashi Tanaka Hisashi Tanaka Yeon-Joo Lee Wei Yuan Johann S. de Bono Johann S. de Bono Irina Vasilevskaya Karen E. Knudsen Michael R. Freeman Stephen J. Freedland Stephen J. Freedland |
| author_sort | Gloria Cecilia Galvan |
| collection | DOAJ |
| description | IntroductionWe previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.MethodsWe employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays.ResultsTranscriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced “BRCAness” by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects.DiscussionThese results suggest 27HC induces “BRCAness”, a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC. |
| first_indexed | 2024-03-07T21:34:09Z |
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| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-07T21:34:09Z |
| publishDate | 2023-12-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-ec60d6dd2eac4bd18a56190427b615e92024-02-26T14:42:47ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-12-011310.3389/fonc.2023.1251297125129727-hydroxycholesterol and DNA damage repair: implication in prostate cancerGloria Cecilia Galvan0Nadine A. Friedrich1Sanjay Das2Sanjay Das3Sanjay Das4James P. Daniels5Sara Pollan6Shweta Dambal7Ryusuke Suzuki8Sergio E. Sanders9Sungyong You10Hisashi Tanaka11Hisashi Tanaka12Yeon-Joo Lee13Wei Yuan14Johann S. de Bono15Johann S. de Bono16Irina Vasilevskaya17Karen E. Knudsen18Michael R. Freeman19Stephen J. Freedland20Stephen J. Freedland21Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, University of California, Los Angeles, Los Angeles, CA, United StatesUrology Section, Department of Surgery, Veterans Affairs Health Care System, Durham, NC, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Pathology, Duke University School of Medicine, Durham, NC, United StatesDepartment of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesCancer Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research, London, United KingdomCancer Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research, London, United KingdomProstate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, United KingdomDepartment of Cancer Biology at Thomas Jefferson University, Philadelphia, PA, United StatesDepartment of Cancer Biology at Thomas Jefferson University, Philadelphia, PA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesDepartment of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United StatesUrology Section, Department of Surgery, Veterans Affairs Health Care System, Durham, NC, United StatesIntroductionWe previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.MethodsWe employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays.ResultsTranscriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced “BRCAness” by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects.DiscussionThese results suggest 27HC induces “BRCAness”, a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.https://www.frontiersin.org/articles/10.3389/fonc.2023.1251297/full27-hydroxycholesterol (27HC)prostate cancerhydroxycholesterolLNCaP (prostate cancer cell)CYP27A1DU145 (prostate) cancer cell line |
| spellingShingle | Gloria Cecilia Galvan Nadine A. Friedrich Sanjay Das Sanjay Das Sanjay Das James P. Daniels Sara Pollan Shweta Dambal Ryusuke Suzuki Sergio E. Sanders Sungyong You Hisashi Tanaka Hisashi Tanaka Yeon-Joo Lee Wei Yuan Johann S. de Bono Johann S. de Bono Irina Vasilevskaya Karen E. Knudsen Michael R. Freeman Stephen J. Freedland Stephen J. Freedland 27-hydroxycholesterol and DNA damage repair: implication in prostate cancer Frontiers in Oncology 27-hydroxycholesterol (27HC) prostate cancer hydroxycholesterol LNCaP (prostate cancer cell) CYP27A1 DU145 (prostate) cancer cell line |
| title | 27-hydroxycholesterol and DNA damage repair: implication in prostate cancer |
| title_full | 27-hydroxycholesterol and DNA damage repair: implication in prostate cancer |
| title_fullStr | 27-hydroxycholesterol and DNA damage repair: implication in prostate cancer |
| title_full_unstemmed | 27-hydroxycholesterol and DNA damage repair: implication in prostate cancer |
| title_short | 27-hydroxycholesterol and DNA damage repair: implication in prostate cancer |
| title_sort | 27 hydroxycholesterol and dna damage repair implication in prostate cancer |
| topic | 27-hydroxycholesterol (27HC) prostate cancer hydroxycholesterol LNCaP (prostate cancer cell) CYP27A1 DU145 (prostate) cancer cell line |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1251297/full |
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