SRSF1 and RBM4 differentially modulate the oncogenic effect of HIF-1α in lung cancer cells through alternative splicing mechanism

Huai Liang Chang, Jung Chun Lin

Research output: Contribution to journalArticle

Abstract

Alternative splicing (AS) constitutes a pivotal mechanism for expanding the transcriptome and proteome diversity in higher eukaryotes. In contrast, misregulated AS events are relevant to carcinogenic signatures, including migration, angiogenesis, immortality, and drug resistance of cancer cells. Using a transcriptome analysis, discriminative splicing profiles of hypoxia-inducible factor (HIF)-1α transcripts were identified in tumorous tissues compared to adjacent normal tissues of lung cancer (LC) patients. In cancerous tissues or LC-derived cells, relatively high levels of HIF-1α-ex14 transcripts encoding the HIF-1αS isoform were noted compared to adjacent normal tissues and non-cancerous cells. The HIF-1αS isoform exhibited a more-prominent effect than that of the HIF-1αL isoform translated from HIF-1α+ex14 transcripts on enhancing promoter activities of the vascular endothelial growth factor receptor 2 (VEGFR2), serine/arginine splicing factor 1 (SRSF1), and c13orf25 genes. An increase in the SRSF1 protein facilitated the generation of HIF-1α-ex14 transcripts, whereas overexpression of RNA-binding motif protein 4 (RBM4) enhanced the expression of HIF-1α+ex14 transcripts in the A549 cells. Results of splicing reporter assays demonstrated the differential impacts of RBM4 and SRSF1 on the utilization of HIF-1α exon 14 in a CU element-dependent manner. In addition to transcriptional regulation, overexpression of the HIF-1αS and HIF-1αL isoforms differentially enhanced the metastatic signatures of A549 cells. Taken together, SRSF1 and RBM4 constitute an antagonistic mechanism on regulating the splicing profiles of HIF-1α gene, which is relevant to the oncogenic signatures of LC cells.

Original languageEnglish
Article number118550
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number12
DOIs
Publication statusPublished - Dec 1 2019

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Hypoxia-Inducible Factor 1
RNA-Binding Proteins
Alternative Splicing
Lung Neoplasms
Protein Isoforms
Vascular Endothelial Growth Factor Receptor-2
Gene Expression Profiling
Proteome
Serine-Arginine Splicing Factors
RNA-Binding Motifs
Eukaryota
Transcriptome
Drug Resistance
Genes
Exons
Hypoxia

Keywords

  • A549
  • Alternative splicing
  • HIF-1α
  • RBM4
  • SRSF1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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title = "SRSF1 and RBM4 differentially modulate the oncogenic effect of HIF-1α in lung cancer cells through alternative splicing mechanism",
abstract = "Alternative splicing (AS) constitutes a pivotal mechanism for expanding the transcriptome and proteome diversity in higher eukaryotes. In contrast, misregulated AS events are relevant to carcinogenic signatures, including migration, angiogenesis, immortality, and drug resistance of cancer cells. Using a transcriptome analysis, discriminative splicing profiles of hypoxia-inducible factor (HIF)-1α transcripts were identified in tumorous tissues compared to adjacent normal tissues of lung cancer (LC) patients. In cancerous tissues or LC-derived cells, relatively high levels of HIF-1α-ex14 transcripts encoding the HIF-1αS isoform were noted compared to adjacent normal tissues and non-cancerous cells. The HIF-1αS isoform exhibited a more-prominent effect than that of the HIF-1αL isoform translated from HIF-1α+ex14 transcripts on enhancing promoter activities of the vascular endothelial growth factor receptor 2 (VEGFR2), serine/arginine splicing factor 1 (SRSF1), and c13orf25 genes. An increase in the SRSF1 protein facilitated the generation of HIF-1α-ex14 transcripts, whereas overexpression of RNA-binding motif protein 4 (RBM4) enhanced the expression of HIF-1α+ex14 transcripts in the A549 cells. Results of splicing reporter assays demonstrated the differential impacts of RBM4 and SRSF1 on the utilization of HIF-1α exon 14 in a CU element-dependent manner. In addition to transcriptional regulation, overexpression of the HIF-1αS and HIF-1αL isoforms differentially enhanced the metastatic signatures of A549 cells. Taken together, SRSF1 and RBM4 constitute an antagonistic mechanism on regulating the splicing profiles of HIF-1α gene, which is relevant to the oncogenic signatures of LC cells.",
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AU - Chang, Huai Liang

AU - Lin, Jung Chun

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N2 - Alternative splicing (AS) constitutes a pivotal mechanism for expanding the transcriptome and proteome diversity in higher eukaryotes. In contrast, misregulated AS events are relevant to carcinogenic signatures, including migration, angiogenesis, immortality, and drug resistance of cancer cells. Using a transcriptome analysis, discriminative splicing profiles of hypoxia-inducible factor (HIF)-1α transcripts were identified in tumorous tissues compared to adjacent normal tissues of lung cancer (LC) patients. In cancerous tissues or LC-derived cells, relatively high levels of HIF-1α-ex14 transcripts encoding the HIF-1αS isoform were noted compared to adjacent normal tissues and non-cancerous cells. The HIF-1αS isoform exhibited a more-prominent effect than that of the HIF-1αL isoform translated from HIF-1α+ex14 transcripts on enhancing promoter activities of the vascular endothelial growth factor receptor 2 (VEGFR2), serine/arginine splicing factor 1 (SRSF1), and c13orf25 genes. An increase in the SRSF1 protein facilitated the generation of HIF-1α-ex14 transcripts, whereas overexpression of RNA-binding motif protein 4 (RBM4) enhanced the expression of HIF-1α+ex14 transcripts in the A549 cells. Results of splicing reporter assays demonstrated the differential impacts of RBM4 and SRSF1 on the utilization of HIF-1α exon 14 in a CU element-dependent manner. In addition to transcriptional regulation, overexpression of the HIF-1αS and HIF-1αL isoforms differentially enhanced the metastatic signatures of A549 cells. Taken together, SRSF1 and RBM4 constitute an antagonistic mechanism on regulating the splicing profiles of HIF-1α gene, which is relevant to the oncogenic signatures of LC cells.

AB - Alternative splicing (AS) constitutes a pivotal mechanism for expanding the transcriptome and proteome diversity in higher eukaryotes. In contrast, misregulated AS events are relevant to carcinogenic signatures, including migration, angiogenesis, immortality, and drug resistance of cancer cells. Using a transcriptome analysis, discriminative splicing profiles of hypoxia-inducible factor (HIF)-1α transcripts were identified in tumorous tissues compared to adjacent normal tissues of lung cancer (LC) patients. In cancerous tissues or LC-derived cells, relatively high levels of HIF-1α-ex14 transcripts encoding the HIF-1αS isoform were noted compared to adjacent normal tissues and non-cancerous cells. The HIF-1αS isoform exhibited a more-prominent effect than that of the HIF-1αL isoform translated from HIF-1α+ex14 transcripts on enhancing promoter activities of the vascular endothelial growth factor receptor 2 (VEGFR2), serine/arginine splicing factor 1 (SRSF1), and c13orf25 genes. An increase in the SRSF1 protein facilitated the generation of HIF-1α-ex14 transcripts, whereas overexpression of RNA-binding motif protein 4 (RBM4) enhanced the expression of HIF-1α+ex14 transcripts in the A549 cells. Results of splicing reporter assays demonstrated the differential impacts of RBM4 and SRSF1 on the utilization of HIF-1α exon 14 in a CU element-dependent manner. In addition to transcriptional regulation, overexpression of the HIF-1αS and HIF-1αL isoforms differentially enhanced the metastatic signatures of A549 cells. Taken together, SRSF1 and RBM4 constitute an antagonistic mechanism on regulating the splicing profiles of HIF-1α gene, which is relevant to the oncogenic signatures of LC cells.

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