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

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:81

Enthalten in:

Cancer research - 81(2021), 7 vom: 01. Apr., Seite 1827-1839

Sprache:

Englisch

Beteiligte Personen:

Lucchesi, Christopher A [VerfasserIn]
Zhang, Jin [VerfasserIn]
Ma, Buyong [VerfasserIn]
Nussinov, Ruth [VerfasserIn]
Chen, Xinbin [VerfasserIn]

Links:

Volltext

Themen:

AGO2 protein, human
Argonaute Proteins
BIRC5 protein, human
Imidazoles
Journal Article
MIRN203 microRNA, human
MicroRNAs
Mirnlet7 microRNA, human
Naphthoquinones
RBM38 protein, human
RNA-Binding Proteins
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Sepantronium
Survivin
UZ77T1VFBM

Anmerkungen:

Date Completed 11.08.2021

Date Revised 16.02.2024

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1158/0008-5472.CAN-20-3157

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM320352501