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In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAFV600E in melanoma.

Guo X, Xu Y, Zhao Z - Mol. Cancer (2015)

Bottom Line: This might be due to BRAF dysregulation of DNMT3A, which was identified as a potential target with significant down-regulation in BRAF (V600E).Finally, we demonstrated that BRAF (V600E) targets may play essential functional roles in cell growth and proliferation, measured by their effects on melanoma tumor growth using a short hairpin RNA silencing experimental dataset.Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. xingyi.guo@vanderbilt.edu.

ABSTRACT

Background: The recurrent BRAF driver mutation V600E (BRAF (V600E)) is currently one of the most clinically relevant mutations in melanoma. However, the genome-wide transcriptional and epigenetic dysregulations induced by BRAF (V600E) are still unclear. The investigation of this driver mutation's functional consequences is critical to the understanding of tumorigenesis and the development of therapeutic strategies.

Methods and results: We performed an integrative analysis of transcriptomic and epigenomic changes disturbed by BRAF (V600E) by comparing the gene expression and methylation profiles of 34 primary cutaneous melanoma tumors harboring BRAF (V600E) with those of 27 BRAF (WT) samples available from The Cancer Genome Atlas (TCGA). A total of 711 significantly differentially expressed genes were identified as putative BRAF (V600E) target genes. Functional enrichment analyses revealed the transcription factor MITF (p < 3.6 × 10(-16)) and growth factor TGFB1 (p < 3.1 × 10(-9)) were the most significantly enriched up-regulators, with MITF being significantly up-regulated, whereas TGFB1 was significantly down-regulated in BRAF (V600E), suggesting that they may mediate tumorigenesis driven by BRAF (V600E). Further investigation using the MITF ChIP-Seq data confirmed that BRAF (V600E) led to an overall increased level of gene expression for the MITF targets. Furthermore, DNA methylation analysis revealed a global DNA methylation loss in BRAF (V600E) relative to BRAF (WT). This might be due to BRAF dysregulation of DNMT3A, which was identified as a potential target with significant down-regulation in BRAF (V600E). Finally, we demonstrated that BRAF (V600E) targets may play essential functional roles in cell growth and proliferation, measured by their effects on melanoma tumor growth using a short hairpin RNA silencing experimental dataset.

Conclusions: Our integrative analysis identified a set of BRAF (V600E) target genes. Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.

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BRAFV600Etarget genes in melanoma cell proliferation. Boxplots of shRNA values (measuring melanoma relative cell proliferation) for BRAFV600E target genes in down-regulation (D), up-regulation (U), and control genes (C). BRAFV600E target genes in down-regulations showed a statistically significant increase of melanoma cell proliferation relative to the control, whereas up-regulation genes exhibited a slight decrease in melanoma cell proliferation.
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Fig7: BRAFV600Etarget genes in melanoma cell proliferation. Boxplots of shRNA values (measuring melanoma relative cell proliferation) for BRAFV600E target genes in down-regulation (D), up-regulation (U), and control genes (C). BRAFV600E target genes in down-regulations showed a statistically significant increase of melanoma cell proliferation relative to the control, whereas up-regulation genes exhibited a slight decrease in melanoma cell proliferation.

Mentions: We have shown that putative BRAFV600E target genes may play essential roles in melanoma tumorigenesis. To further verify the effects of those genes on cancer cell proliferation, we used a publicly available, large-scale gene silencing dataset from the short hairpin RNA (shRNA) screens of three melanoma cell lines (see Materials and methods, [45]). Among the 711 putative BRAFV600E target genes, we found that down-regulated genes significantly increased cell growth and proliferation, whereas up-regulated genes slightly decreased both (Figure 7). According to the effects of putative BRAFV600E targets on melanoma cell proliferation, we identified top tumor suppressor genes including TGFB1, TGFB1I1, PRODH, NAT6, ZNF205, ZNF142, FRS3, RUNX3, IGFBP5, HPGD, MAPK11, and NFIC, which significantly increased cell growth and proliferations. In contrast, top oncogenes including MET, BFSP1, CDH19, and ST6GALNAC3 were found to be associated with decreased cell growth and proliferations. In summary, our results suggest that BRAFV600E may play essential functional roles in cell growth and proliferation.Figure 7


In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAFV600E in melanoma.

Guo X, Xu Y, Zhao Z - Mol. Cancer (2015)

BRAFV600Etarget genes in melanoma cell proliferation. Boxplots of shRNA values (measuring melanoma relative cell proliferation) for BRAFV600E target genes in down-regulation (D), up-regulation (U), and control genes (C). BRAFV600E target genes in down-regulations showed a statistically significant increase of melanoma cell proliferation relative to the control, whereas up-regulation genes exhibited a slight decrease in melanoma cell proliferation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4373107&req=5

Fig7: BRAFV600Etarget genes in melanoma cell proliferation. Boxplots of shRNA values (measuring melanoma relative cell proliferation) for BRAFV600E target genes in down-regulation (D), up-regulation (U), and control genes (C). BRAFV600E target genes in down-regulations showed a statistically significant increase of melanoma cell proliferation relative to the control, whereas up-regulation genes exhibited a slight decrease in melanoma cell proliferation.
Mentions: We have shown that putative BRAFV600E target genes may play essential roles in melanoma tumorigenesis. To further verify the effects of those genes on cancer cell proliferation, we used a publicly available, large-scale gene silencing dataset from the short hairpin RNA (shRNA) screens of three melanoma cell lines (see Materials and methods, [45]). Among the 711 putative BRAFV600E target genes, we found that down-regulated genes significantly increased cell growth and proliferation, whereas up-regulated genes slightly decreased both (Figure 7). According to the effects of putative BRAFV600E targets on melanoma cell proliferation, we identified top tumor suppressor genes including TGFB1, TGFB1I1, PRODH, NAT6, ZNF205, ZNF142, FRS3, RUNX3, IGFBP5, HPGD, MAPK11, and NFIC, which significantly increased cell growth and proliferations. In contrast, top oncogenes including MET, BFSP1, CDH19, and ST6GALNAC3 were found to be associated with decreased cell growth and proliferations. In summary, our results suggest that BRAFV600E may play essential functional roles in cell growth and proliferation.Figure 7

Bottom Line: This might be due to BRAF dysregulation of DNMT3A, which was identified as a potential target with significant down-regulation in BRAF (V600E).Finally, we demonstrated that BRAF (V600E) targets may play essential functional roles in cell growth and proliferation, measured by their effects on melanoma tumor growth using a short hairpin RNA silencing experimental dataset.Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. xingyi.guo@vanderbilt.edu.

ABSTRACT

Background: The recurrent BRAF driver mutation V600E (BRAF (V600E)) is currently one of the most clinically relevant mutations in melanoma. However, the genome-wide transcriptional and epigenetic dysregulations induced by BRAF (V600E) are still unclear. The investigation of this driver mutation's functional consequences is critical to the understanding of tumorigenesis and the development of therapeutic strategies.

Methods and results: We performed an integrative analysis of transcriptomic and epigenomic changes disturbed by BRAF (V600E) by comparing the gene expression and methylation profiles of 34 primary cutaneous melanoma tumors harboring BRAF (V600E) with those of 27 BRAF (WT) samples available from The Cancer Genome Atlas (TCGA). A total of 711 significantly differentially expressed genes were identified as putative BRAF (V600E) target genes. Functional enrichment analyses revealed the transcription factor MITF (p < 3.6 × 10(-16)) and growth factor TGFB1 (p < 3.1 × 10(-9)) were the most significantly enriched up-regulators, with MITF being significantly up-regulated, whereas TGFB1 was significantly down-regulated in BRAF (V600E), suggesting that they may mediate tumorigenesis driven by BRAF (V600E). Further investigation using the MITF ChIP-Seq data confirmed that BRAF (V600E) led to an overall increased level of gene expression for the MITF targets. Furthermore, DNA methylation analysis revealed a global DNA methylation loss in BRAF (V600E) relative to BRAF (WT). This might be due to BRAF dysregulation of DNMT3A, which was identified as a potential target with significant down-regulation in BRAF (V600E). Finally, we demonstrated that BRAF (V600E) targets may play essential functional roles in cell growth and proliferation, measured by their effects on melanoma tumor growth using a short hairpin RNA silencing experimental dataset.

Conclusions: Our integrative analysis identified a set of BRAF (V600E) target genes. Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.

Show MeSH
Related in: MedlinePlus