1,25-Dihydroxyvitamin D3 Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line

Jabril R. Johnson; Rachel N. Martini; Yate Ching Yuan; Leanne Woods-Burnham; Mya Walker; Greisha L. Ortiz-Hernandez; Firas Kobeissy; Dorothy Galloway; Amani Gaddy; Chidinma Oguejiofor; Blake Allen; Deyana Lewis; Melissa B. Davis; K. Sean Kimbro; Clayton C. Yates; Adam B. Murphy; Rick A. Kittles

doi:10.3390/biology13050346

1,25-Dihydroxyvitamin D₃ Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line

Jabril R. Johnson^*, Rachel N. Martini, Yate Ching Yuan, Leanne Woods-Burnham, Mya Walker, Greisha L. Ortiz-Hernandez, Firas Kobeissy, Dorothy Galloway, Amani Gaddy, Chidinma Oguejiofor, Blake Allen, Deyana Lewis, Melissa B. Davis, K. Sean Kimbro, Clayton C. Yates, Adam B. Murphy, Rick A. Kittles

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

Abstract

Vitamin D₃ is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D₃ deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D₃ metabolite, 1α,25(OH)₂D₃, at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH)₂D₃ treatment. Pathway enrichment analysis predicted 1α,25(OH)₂D_3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (p < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH)₂D₃ treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (p < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH)₂D₃ regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH)₂D₃ could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men.

Original language	English (US)
Article number	346
Journal	Biology
Volume	13
Issue number	5
DOIs	https://doi.org/10.3390/biology13050346
State	Published - May 2024

Funding

We want to thank Madhavi Bathina for her technical expertise and assistance. We want to thank City of Hope\u2019s Integrative Genomics Core (IGC) for performing RNA sequencing and the Biomedical Informatics Core for bioinformatic analytics. The authors acknowledge the leadership and staff of the City of Hope Center for Informatics for POSEIDON (Precision Oncology Software Environment Interoperable Data Ontologies Network) data exploration, visualization, and analysis; access to the HPRCC (High-Performance Research Compute Center) resource; and TBI (Translational Bioinformatics) support and training. Lastly, we would like to thank the support of Morehouse School of Medicine\u2019s Research Centers Minority Institutions (RCMI) and the Institute of Translational Genomic Medicine (ITGM). Author J.R.J. received research support from the NIH/NCI U54CA118638. Author L.W.-B. received research support from the NIH 1T32CA186895, NIH KL2TR002381, and the Prostate Cancer Foundation 20YOUN04. Author G.L.O.-H. received research support from the T32 CA221709/CA/NCI NIH. Author M.B.D. received research support from the Prostate SPORE Award 5 P50 CA211024-04. Author C.C.Y. received research support from the CDMRP-PC190741. Author A.B.M. received research support from the U.S. Department of Veteran Affairs IK2CX000926. Lastly, author J.R.J., L.W.-B., F.K. and K.S.K. received research support from the NIH/NIMHD 2U54MD007602.

Keywords

ANLN
ECT2
RNA-Seq
Rho GTPase
actin cytoskeleton
calcitriol
cell cycle
non-malignant prostate cell
prostate cancer disparities
vitamin D

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Agricultural and Biological Sciences

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/biology13050346

Cite this

Johnson, J. R., Martini, R. N., Yuan, Y. C., Woods-Burnham, L., Walker, M., Ortiz-Hernandez, G. L., Kobeissy, F., Galloway, D., Gaddy, A., Oguejiofor, C., Allen, B., Lewis, D., Davis, M. B., Kimbro, K. S., Yates, C. C., Murphy, A. B., & Kittles, R. A. (2024). 1,25-Dihydroxyvitamin D₃ Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line. Biology, 13(5), Article 346. https://doi.org/10.3390/biology13050346

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title = "1,25-Dihydroxyvitamin D3 Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line",

abstract = "Vitamin D3 is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D3 deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D3 metabolite, 1α,25(OH)2D3, at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH)2D3 treatment. Pathway enrichment analysis predicted 1α,25(OH)2D3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (p < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH)2D3 treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (p < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH)2D3 regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH)2D3 could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men.",

keywords = "ANLN, ECT2, RNA-Seq, Rho GTPase, actin cytoskeleton, calcitriol, cell cycle, non-malignant prostate cell, prostate cancer disparities, vitamin D",

author = "Johnson, {Jabril R.} and Martini, {Rachel N.} and Yuan, {Yate Ching} and Leanne Woods-Burnham and Mya Walker and Ortiz-Hernandez, {Greisha L.} and Firas Kobeissy and Dorothy Galloway and Amani Gaddy and Chidinma Oguejiofor and Blake Allen and Deyana Lewis and Davis, {Melissa B.} and Kimbro, {K. Sean} and Yates, {Clayton C.} and Murphy, {Adam B.} and Kittles, {Rick A.}",

note = "Publisher Copyright: {\textcopyright} 2024 by the authors.",

year = "2024",

month = may,

doi = "10.3390/biology13050346",

language = "English (US)",

volume = "13",

journal = "Biology",

issn = "2079-7737",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "5",

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Johnson, JR, Martini, RN, Yuan, YC, Woods-Burnham, L, Walker, M, Ortiz-Hernandez, GL, Kobeissy, F, Galloway, D, Gaddy, A, Oguejiofor, C, Allen, B, Lewis, D, Davis, MB, Kimbro, KS, Yates, CC, Murphy, AB & Kittles, RA 2024, '1,25-Dihydroxyvitamin D₃ Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line', Biology, vol. 13, no. 5, 346. https://doi.org/10.3390/biology13050346

TY - JOUR

T1 - 1,25-Dihydroxyvitamin D3 Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line

AU - Johnson, Jabril R.

AU - Martini, Rachel N.

AU - Yuan, Yate Ching

AU - Woods-Burnham, Leanne

AU - Walker, Mya

AU - Ortiz-Hernandez, Greisha L.

AU - Kobeissy, Firas

AU - Galloway, Dorothy

AU - Gaddy, Amani

AU - Oguejiofor, Chidinma

AU - Allen, Blake

AU - Lewis, Deyana

AU - Davis, Melissa B.

AU - Kimbro, K. Sean

AU - Yates, Clayton C.

AU - Murphy, Adam B.

AU - Kittles, Rick A.

PY - 2024/5

Y1 - 2024/5

N2 - Vitamin D3 is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D3 deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D3 metabolite, 1α,25(OH)2D3, at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH)2D3 treatment. Pathway enrichment analysis predicted 1α,25(OH)2D3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (p < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH)2D3 treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (p < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH)2D3 regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH)2D3 could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men.

AB - Vitamin D3 is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D3 deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D3 metabolite, 1α,25(OH)2D3, at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH)2D3 treatment. Pathway enrichment analysis predicted 1α,25(OH)2D3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (p < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH)2D3 treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (p < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH)2D3 regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH)2D3 could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men.

KW - ANLN

KW - ECT2

KW - RNA-Seq

KW - Rho GTPase

KW - actin cytoskeleton

KW - calcitriol

KW - cell cycle

KW - non-malignant prostate cell

KW - prostate cancer disparities

KW - vitamin D

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U2 - 10.3390/biology13050346

DO - 10.3390/biology13050346

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SN - 2079-7737

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