Survivin Expression Is Differentially Regulated by a Selective Cross-talk between RBM38 and miRNAs let-7b or miR-203a
©2021 American Association for Cancer Research..
RNA-binding motif 38 (RBM38) is a member of a protein family with a highly conserved RNA-binding motif and has been shown to regulate mRNA processing, stability, and translation. Survivin is an essential modulator of apoptotic and nonapoptotic cell death as well as a stress responder. Survivin mRNA is the fourth most frequently overexpressed transcript in the human cancer transcriptome, and its aberrant expression is associated with chemo-/radioresistance and poor prognosis. In this study, we examined whether survivin expression is regulated by RBM38. RBM38 bound to survivin 3'-untranslated region and suppressed miRNA let-7b from binding to and degrading survivin mRNA, leading to increased survivin expression. RBM38 interacted with argonaute-2 (AGO2) and facilitated miR-203a-mediated degradation of survivin mRNA, leading to decreased survivin expression. Due to the abundance of let-7b over miR-203a, RBM38 ultimately increased survivin expression in HCT116 and MCF7 cells. In addition, Ser-195 in RBM38 interacted with Glu-73/-76 in AGO2, and Pep8, an eight-amino acid peptide spanning the region of Ser-195 in RBM38, blocked the RBM38-AGO2 interaction and inhibited miR-203a-mediated mRNA degradation, leading to enhanced survivin expression. Furthermore, Pep8 cooperated with YM155, an inhibitor of survivin, to suppress tumor spheroid growth and viability. Pep8 sensitized tumor cells to YM155-induced DNA damage in an RBM38-dependent manner. Together, our data indicate that RBM38 is a dual regulator of survivin and that Pep8/YM155 may be therapeutically explored for tumor suppression. SIGNIFICANCE: These findings show that RBM38 exerts opposing effects on survivin expression via two miRNAs, and disruption of the RBM38-AGO2 complex by an eight-amino acid peptide sensitizes tumor spheroids to survivin inhibitor YM155.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:81 |
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Enthalten in: |
Cancer research - 81(2021), 7 vom: 01. Apr., Seite 1827-1839 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Lucchesi, Christopher A [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 11.08.2021 Date Revised 16.02.2024 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1158/0008-5472.CAN-20-3157 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM320352501 |
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520 | |a RNA-binding motif 38 (RBM38) is a member of a protein family with a highly conserved RNA-binding motif and has been shown to regulate mRNA processing, stability, and translation. Survivin is an essential modulator of apoptotic and nonapoptotic cell death as well as a stress responder. Survivin mRNA is the fourth most frequently overexpressed transcript in the human cancer transcriptome, and its aberrant expression is associated with chemo-/radioresistance and poor prognosis. In this study, we examined whether survivin expression is regulated by RBM38. RBM38 bound to survivin 3'-untranslated region and suppressed miRNA let-7b from binding to and degrading survivin mRNA, leading to increased survivin expression. RBM38 interacted with argonaute-2 (AGO2) and facilitated miR-203a-mediated degradation of survivin mRNA, leading to decreased survivin expression. Due to the abundance of let-7b over miR-203a, RBM38 ultimately increased survivin expression in HCT116 and MCF7 cells. In addition, Ser-195 in RBM38 interacted with Glu-73/-76 in AGO2, and Pep8, an eight-amino acid peptide spanning the region of Ser-195 in RBM38, blocked the RBM38-AGO2 interaction and inhibited miR-203a-mediated mRNA degradation, leading to enhanced survivin expression. Furthermore, Pep8 cooperated with YM155, an inhibitor of survivin, to suppress tumor spheroid growth and viability. Pep8 sensitized tumor cells to YM155-induced DNA damage in an RBM38-dependent manner. Together, our data indicate that RBM38 is a dual regulator of survivin and that Pep8/YM155 may be therapeutically explored for tumor suppression. SIGNIFICANCE: These findings show that RBM38 exerts opposing effects on survivin expression via two miRNAs, and disruption of the RBM38-AGO2 complex by an eight-amino acid peptide sensitizes tumor spheroids to survivin inhibitor YM155 | ||
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700 | 1 | |a Ma, Buyong |e verfasserin |4 aut | |
700 | 1 | |a Nussinov, Ruth |e verfasserin |4 aut | |
700 | 1 | |a Chen, Xinbin |e verfasserin |4 aut | |
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