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1. Vitamin D: Possible Therapeutic Roles in Hepatocellular Carcinoma

Author

Isaacson B. Adelani, Oluwakemi A. Rotimi, Emmanuel N. Maduagwu, and Solomon O. Rotimi

Subjects
vitamin D, therapeutic, inflammation, apoptosis, differentiation, proliferation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Hepatocellular carcinoma (HCC) is a unique type of liver cancer instigated by underlying liver diseases. Pre-clinical evidence suggests that HCC progression, like other cancers, could be aided by vitamin D deficiency. Vitamin D is a lipid-soluble hormone usually obtained through sunlight. Vitamin D elucidates its biological responses by binding the vitamin D receptor; thus, promoting skeletal mineralization, and maintain calcium homeostasis. Other reported Vitamin D functions include specific roles in proliferation, angiogenesis, apoptosis, inflammation, and cell differentiation. This review highlighted studies on vitamin D’s functional roles in HCC and discussed the specific therapeutic targets from various in vivo, in vitro and clinical studies over the years. Furthermore, it described recent advancements in vitamin D’s anticancer effects and its metabolizing enzymes’ roles in HCC development. In summary, the review elucidated specific vitamin D-associated target genes that play critical functions in the inhibition of tumorigenesis through inflammation, oxidative stress, invasion, and apoptosis in HCC progression.

Published
2021
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2. Anti-inflammatory and antioxidant activities of fractions and compound from Ricinodendron heudelotii (Baill.)

Author

Omolara F. Yakubu, Abiodun H. Adebayo, Emeka E.J. Iweala, Isaacson B. Adelani, Temitope A. Ishola, and Ying-Jun Zhang

Subjects
Natural product chemistry, Antioxidant, Anti-inflammatory, Ricinodendron heudelotii, Corilagin, Tannins, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Medicinal plants have been documented over the years to play vital role in promoting human health. The study evaluated the anti-inflammatory and anti-oxidant activities of different fractions and isolated compound from Ricinodendron heudelotii leaves. The leaves of Ricinodendron heudelotii were extracted with ethanol and further partitioned sequentially using petroleum ether, ethylacetate and butanol. Bioassay–guided fractionation of the ethylacetate fraction was done using repeated column chromatographic technique while the structural elucidation of pure compound was carried out using mass spectra, 13C and 1H NMR analyses. Antioxidant potential of the fractions and isolated compound were evaluated with 2,2-Azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays and anti-inflammatory effect of fractions was measured by their inhibitory potency on nitric oxide (NO).Corilagin, an amorphous tannin was isolated and structurally elucidated. Corilagin showed scavenging effect against ABTS and DPPH radicals which vary in a dose dependent manner. It also showed an antioxidant potential with IC50 value of 0.003 mg/mL comparable to vitamin C 0.001 mg/mL) used as standard. The butanol and ethylacetate fractions exhibited significant (p < 0.05) NO inhibition of 60 and 69% respectively after treatment of RAW 264.7 macrophages with lipopolysaccharide. These results demonstrated the role of isolated corilagin as a promising potent antioxidant while the ethylacetate and butanol fractions suppressed the expression of an inflammation mediator by inhibiting nitric oxide.

Published
2019
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3. Time-Course Effects of Acute Aflatoxin B1 Exposure on Hepatic Mitochondrial Lipids and Oxidative Stress in Rats

Author

Oluwakemi A. Rotimi, Solomon O. Rotimi, Jaclyn M. Goodrich, Isaacson B. Adelani, Emmanuel Agbonihale, and Gbemisola Talabi

Subjects
aflatoxin B1, liver, mitochondria, lipid, cholesterol, thioredoxin reductase, Therapeutics. Pharmacology, RM1-950
Abstract

Aflatoxins are secondary metabolites of certain Aspergillus species, that contaminate staple foods, particularly in developing countries. Aflatoxin B1 (AFB1) is the most toxic and common of the major types of aflatoxins. AFB1 is hepatotoxic and has been implicated in increasing the risk of hepatocellular carcinoma (HCC). We have previously shown that subacute exposure to AFB1 for 7 days disrupts hepatic lipids; therefore, this study determined the time-course effects of acute aflatoxin exposure on hepatic mitochondrial lipids and oxidative stress. To achieve this, thirty male albino rats were randomly assigned to six groups. The groups received an oral dose of 1 mg/kg body weight AFB1 or vehicle only (controls) for one, four, or seven days, respectively. Twenty-four hours after the last dose, the animals were sacrificed and liver excised. Mitochondria and cytosolic fractions were obtained from the liver after which lipids (cholesterol, triacylglycerols) were determined in the mitochondria while biomarkers of oxidative stress (glutathione, glutathione transferase (GST), glutathione peroxidase (GPx), glutathione reductase, nitric oxide (NO), malonaldehyde (MDA), thioredoxin reductase (TR), and superoxide dismutase (SOD) were determined spectrophotometrically in the mitochondria and cytosolic fractions. The expression of genes (Nrf2, Acc, Nqo1, and HmgCoa) were determined using quantitative RT-PCR. Results showed that AFB1 significantly increased mitochondrial cholesterol at day seven (treatment vs. control, p = 0.016). It also increased the concentrations of NO and MDA at day one and day seven while the activity of GPx and concentration of GSH were increased at day seven (p = 0.030) and day one (p = 0.025) alone, respectively, compared to control. The activities of cytosolic GR (p = 0.014), TR (p = 0.046) and GST (p = 0.044) were increased at day seven. AFB1 significantly increased the expression of Nrf2 (p = 0.029) and decreased the expression of Acc (p = 0.005) at day one. This study revealed that AFB1 disrupts hepatic mitochondrial lipids and antioxidant capacity. These changes were dependent on the timing of exposure and did not follow a linear time-course trend. These alterations could be part of the hepatic mitochondria response mechanism to acute AFB1 toxicity.

Published
2019
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4. African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Manjunath Siddappa, Shahid Hussain, Sajad A. Wani, Jason White, Hancong Tang, Jaimie S. Gray, Hedieh Jafari, Hsu-Chang Wu, Mark D. Long, Isra Elhussin, Balasubramanyam Karanam, Honghe Wang, Rebecca Morgan, Gary Hardiman, Isaacson B. Adelani, Solomon O. Rotimi, Adam R. Murphy, Larisa Nonn, Melissa B. Davis, Rick A. Kittles, Chanita Hughes Halbert, Lara E. Sucheston-Campbell, Clayton Yates, and Moray J. Campbell

Subjects
SDG 3 - Good Health and Well-being
Abstract

African American (AA) prostate cancer associates with vitamin D3 deficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clinical cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correlation analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcriptional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function. Significance: Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.

Published
2023
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5. Supplementary Table 13 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

ST_13 BAZ1A and lineage plasticity

Published
2023
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6. Supplementary Figure 6 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_6 RNA-Seq PCA

Published
2023
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7. Supplementary Figure 8 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_8 RNA-Seq GSEA

Published
2023
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8. Supplementary Figure 13 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_13 GSEA tumors

Published
2023
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9. Supplementary Table 2 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

Supplementary Table _2 - RIME II

Published
2023
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10. Supplementary Table 3 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

ST_3 ATAC-Seq

Published
2023
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11. Supplementary Figure 3 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_3 motifs in ATAC-Seq

Published
2023
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12. Data from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

African American (AA) prostate cancer associates with vitamin D3 deficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clinical cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correlation analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcriptional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function.Significance:Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.

Published
2023
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13. Supplementary Figure 9 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_9 overlap miRNA

Published
2023
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14. Supplementary Table 4 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

ST_4 ChIP-Seq

Published
2023
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15. Supplementary Table 5 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

ST_5 ChromHMM

Published
2023
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16. Supplementary Table 7 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

ST_7 ATAC-Seq to RIME

Published
2023
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17. Supplementary Figure 5 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_5 ChIP-Seq motif

Published
2023
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18. Supplementary Figure 2 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_2 Ancestry cell lines

Published
2023
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19. Supplementary Figure 4 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_4 VDR cistrome

Published
2023
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20. Supplementary Table 6 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

ST_6 ChIP-Seq Motif

Published
2023
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21. Supplementary Table 8 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

ST_8 ATAC/ChIP-Seq to splicing

Published
2023
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22. Supplementary Figure 7 from African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A

Author

Moray J. Campbell, Clayton Yates, Lara E. Sucheston-Campbell, Chanita Hughes Halbert, Rick A. Kittles, Melissa B. Davis, Larisa Nonn, Adam R. Murphy, Solomon O. Rotimi, Isaacson B. Adelani, Gary Hardiman, Rebecca Morgan, Honghe Wang, Balasubramanyam Karanam, Isra Elhussin, Mark D. Long, Hsu-Chang Wu, Hedieh Jafari, Jaimie S. Gray, Hancong Tang, Jason White, Sajad A. Wani, Shahid Hussain, and Manjunath Siddappa

Abstract

SF_7 RNA-Seq volcanos

Published
2023
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23. Contributors

Author

Mohammed Abbas, Isaacson B. Adelani, Gonçalo J.M. Afonso, Shama Ahmad, González-Zamora Alberto, Khashayar Alikarami, Ricardo Alva, Nasrin Amirrajab, Paula B. Andrade, Ana Cristina Andreazza, Amir Chakeri Ansari, Michael Aschner, Milad Ashrafizadeh, Olivia R.M. Bagshaw, Daniel José Barbosa, Sergio Barroso, Amirhossein Bazmi, Faten F. Bin Dayel, Mélanie Blanc-Legendre, Revathi Boyina, Helena Carmo, Félix Carvalho, Amy E. Chadwick, Yi Chen, Paolo Convertini, Teresa Cunha-Oliveira, Dennis Guilherme da Costa Silva, Majid Darroudi, Lidia de Bari, Patrícia de Brum Vieira, Opeyemi C. De Campos, Mohammad Amin Dehghani, Nancy D. Denslow, Fernanda Carolina Ribeiro Dias, Sujatha Dodoala, Jaroslaw W. Drelich, Ríos-Sánchez Efraín, Dana El Soufi El Sabbagh, Tim L. Emmerzaal, Tahereh Farkhondeh, González-Delgado María Fernanda, Jeferson Luis Franco, Bernard Fromenty, Georgina L. Gardner, Glòria Garrabou, Alessandra Ghigo, Sumalatha Gindi, Jeremy Goldman, Reza Heidari, Vittoria Infantino, Rebecca L. Jensen, Miklós Péter Kalapos, Robyn T. Kiy, Camila Kochi, Tamas Kozicz, Graziela Domingues de Almeida Lima, Thania Rios Rossi Lima, Jiawen Lu, Ulrike Luderer, Mariana Machado-Neves, Kelli F. Malott, M. Manuel Oliveira, Christopher J. Martyniuk, Jennifer McDonough, Daniela Mendes, Chris Moffatt, Eva Morava, Alessandra Murabito, Chunchao Nie, Hossein Niknahad, Mauro Eugenio Medina Nunes, Tolulope D. Olawole, Margrethe A. Olesen, Paulo J. Oliveira, Mohammad Mehdi Ommati, Francisco Peixoto, Lílian Cristina Pereira, Sonia L.C. Pinho, Tina Podinić, Ada Popolo, Jalal Pourahmad, Graeme Preston, Rodrigo A. Quintanilla, Sandeep Raha, Shamima Rahman, Pérez-Morales Rebeca, Iara Magalhães Ribeiro, Joyce Santana Rizzi, Oluwakemi A. Rotimi, Solomon O. Rotimi, Michele Russo, Ali Sabahi, Samina Salim, Saeed Samarghandian, Melania Santer, Danielle Gabriel Seloto, Enayatollah Seydi, Mónica G. Silva, Rui F. Simões, Ana Cláudia Ferreira Souza, Sarah Sternbach, Jeffrey A. Stuart, Marjan Talebi, Simona Todisco, Atefeh Raesi Vanani, and Romeu A. Videira

Published
2023
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26. Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A

Author

Manjunath Siddappa, Shahid Hussain, Sajad A. Wani, Hancong Tang, Jaimie S. Gray, Hedieh Jafari, Hsuchang Wu, Mark D. Long, Isra Elhussin, Balasubramanyam Karanam, Honghe Wang, Rebecca Morgan, Gary Hardiman, Isaacson B. Adelani, Solomon O. Rotimi, Adam R Murphy, Larisa Nonn, Melissa B Davis, Rick A Kittles, Chanita Hughes Halbert, Lara E. Sucheston-Campbell, Clayton Yates, and Moray J. Campbell

Abstract

BackgroundAfrican American (AA) prostate cancer (PCa) appears uniquely sensitive to 1α,25(OH)2D3 signaling, compared to European American (EA) PCa, but the extent and impact of vitamin D receptor genomic functions remain poorly defined.ResultsA panel of EA and AA prostate epithelial cells (EA: HPr1-AR, LNCaP, AA: RC43N, RC43T, RC77N, RC77T) were analyzed with RIME to reveal the cell-specific composition of the VDR- complex. 1α,25(OH)2D3-dependent ATAC-Seq revealed the greatest impact on nucleosome positioning in RC43N and RC43T, with gain of nucleosome-free at enhancer regions. VDR ChIP-Seq identified stronger and more frequent VDR binding in RC43N and RC43T that was enriched for a larger and distinct motif repertoire, than EA cells. VDR binding significantly overlapped with core circadian rhythm transcription factors in AA cell line models. RNA-Seq also revealed significantly stronger 1α,25(OH)2D3 dependent VDR transcriptional responses enriched for circadian rhythm and inflammation networks in AA cells. Whilst RC43N was most responsive, RC43T displayed distorted responses. Significantly reduced BAZ1A/SMARCA5 in AA PCa samples was identified, and restored BAZ1A expression uniquely and significantly increased 1α,25(OH)2D3-regulated VDR targets in AA cells. These VDR- dependent cistrome-annotated genes were also uniquely and most significantly identified in three cohorts of AA PCa patients.ConclusionThese data suggest VDR transcriptional control in the prostate is more potent and dynamic in AA men, and primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmentally-regulated serum vitamin D3 levels suppress these actions. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes including stress responses, access to quality early detection and treatment, social determinants and that collectively contribute to PCa health disparities.

Published
2022
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27. Abstract 3619: Vitamin D receptor function in African American prostate cancer is disrupted by reduced BAZ1A/SMARCA5

Author

Shahid Hussain, Manjunath Siddappa, Sajad A. Wani, Hedieh Jafari, Jaimie S. Gray, Hsu-Chang Wu, Hancong Tang, Mark D. Long, Isra Elhussin, Balasubramanyam Karanam, Honghe Wang, Rebecca Morgan, Gary Hardiman, Isaacson B. Adelani, Rotimi Oladapo, Adam R. Murphy, James R. Marshall, Chanita Highes Halbert, Lara E. Sucheston-Campbell, Clayton Yates, and Moray J. Campbell

Subjects
Cancer Research, Oncology
Abstract

The biological drivers of prostate cancer (PCa) health disparities remain enigmatic. There are genomic differences, for example in the incidence of TMPRSS2 and ERG gene fusions which differ between European American (EA) and African American (AA) PCa. Accumulating epidemiological evidence suggests loss of vitamin D receptor VDR signaling contributes to AA PCa. Therefore, we investigated the VDR signaling in AA and EA prostate models. VDR protein levels were comparable between AA (RC43N, RC43T, RC77N, RC77T) and EA cells (HPr1AR, LNCaP) but RIME analyses identified significant AA-EA differences in VDR binding of coactivators (e.g. NCOA5), corepressors (e.g. HDAC2), and components of SWI/SNF and circadian rhythm complexes. ATAC-Seq identified 1α,25(OH)2D3-stimulated gain in nucleosome free (NF) regions was greatest in RC43N (non-malignant AA cells) and enriched for circadian rhythm transcription motifs (e.g. CLOCK). In RC43T AA PCa cells 1α,25(OH)2D3 led to a loss of NF free regions. Similarly, VDR ChIP-Seq revealed the cistrome was greater in AA cell models, and was dynamically altered in RC43N cells by 1α,25(OH)2D3 and overlapped with the SWI/SNF component SMARCA4, but 1α,25(OH)2D3 led to reduced VDR binding in RC43T cells. The 1α,25(OH)2D3-regulated transcriptome was largest in RC43N and RC43T but GSEA terms were frequently and oppositely enriched, for example Reactome S phase genes were negatively enriched in RC43N, but positively enriched in RC43T. Cistrome-transcriptome integration identified the most significant relationships between VDR binding and the magnitude of 1α,25(OH)2D3-regulated genes in RC43N. Global coregulator analyses identified significantly reduced BAZ1A/SMARCA5 in AA PCa in TCGA and a published cohort of ~1500 AA/EA tumors. Restoring BAZ1A expression in cells resulted in significantly enhanced 1α,25(OH)2D3-regulated transcriptome in RC43N and RC43T cells, and hypergeometric tests revealed the significant enrichment of direct VDR target genes. The footprint of altered AA VDR signaling was evident in three previously established clinical cohorts. Serum miRNA that predicted AA progression from HGPIN to PCa were enriched for 1α,25(OH)2D3-regulated VDR targets; AA tumors from a vitaminD3-treated chemotherapy trail were enriched for VDR-bound genes; and, tumors from men with low serum 25(OH)D3 levels were significantly enriched for VDR target genes identified in AA but not EA PCa. Together, these data suggest VDR transcriptional control is most potent and dynamic in AA prostate cells, and is primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmental-regulated serum vitamin D3 levels most acutely suppress these actions in AA PCa. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes that contributes to PCa health disparities. Citation Format: Shahid Hussain, Manjunath Siddappa, Sajad A. Wani, Hedieh Jafari, Jaimie S. Gray, Hsu-Chang Wu, Hancong Tang, Mark D. Long, Isra Elhussin, Balasubramanyam Karanam, Honghe Wang, Rebecca Morgan, Gary Hardiman, Isaacson B. Adelani, Rotimi Oladapo, Adam R. Murphy, James R. Marshall, Chanita Highes Halbert, Lara E. Sucheston-Campbell, Clayton Yates, Moray J. Campbell. Vitamin D receptor function in African American prostate cancer is disrupted by reduced BAZ1A/SMARCA5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3619.

Published
2022
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