The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry
In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastati...
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| Format: | Article |
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MDPI AG
2020-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/12/2690 |
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| author | Mónica Fernández-Cortés Eduardo Andrés-León Francisco Javier Oliver |
| author_facet | Mónica Fernández-Cortés Eduardo Andrés-León Francisco Javier Oliver |
| author_sort | Mónica Fernández-Cortés |
| collection | DOAJ |
| description | In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs. Finally, we predicted that olaparib-modulated lncRNAs could further regulate several transcription factors and their subsequent target genes in melanoma, suggesting that olaparib may trigger a major shift in gene expression mediated by the regulation lncRNA. Globally, olaparib changed the lncRNA expression landscape during VM affecting angiogenesis-related genes. |
| first_indexed | 2024-03-10T14:04:12Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T14:04:12Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-b43b435dd9ec4ac6a11ba5d40f9756b52023-11-21T00:52:13ZengMDPI AGCells2073-44092020-12-01912269010.3390/cells9122690The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic MimicryMónica Fernández-Cortés0Eduardo Andrés-León1Francisco Javier Oliver2Instituto de Parasitología y Biomedicina López Neyra, CSIC, CIBERONC, 18016 Granada, SpainInstituto de Parasitología y Biomedicina López Neyra, CSIC, CIBERONC, 18016 Granada, SpainInstituto de Parasitología y Biomedicina López Neyra, CSIC, CIBERONC, 18016 Granada, SpainIn highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs. Finally, we predicted that olaparib-modulated lncRNAs could further regulate several transcription factors and their subsequent target genes in melanoma, suggesting that olaparib may trigger a major shift in gene expression mediated by the regulation lncRNA. Globally, olaparib changed the lncRNA expression landscape during VM affecting angiogenesis-related genes.https://www.mdpi.com/2073-4409/9/12/2690vasculogenic mimicrylncRNA integrative analysisuveal melanomaolaparibPARP inhibitors |
| spellingShingle | Mónica Fernández-Cortés Eduardo Andrés-León Francisco Javier Oliver The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry Cells vasculogenic mimicry lncRNA integrative analysis uveal melanoma olaparib PARP inhibitors |
| title | The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry |
| title_full | The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry |
| title_fullStr | The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry |
| title_full_unstemmed | The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry |
| title_short | The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry |
| title_sort | parp inhibitor olaparib modulates the transcriptional regulatory networks of long non coding rnas during vasculogenic mimicry |
| topic | vasculogenic mimicry lncRNA integrative analysis uveal melanoma olaparib PARP inhibitors |
| url | https://www.mdpi.com/2073-4409/9/12/2690 |
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