TY - JOUR
T1 - Survivin expression is differentially regulated by a selective cross-talk between RBM38 and miRNAS let-7b or miR-203a
AU - Lucchesi, Christopher A.
AU - Zhang, Jin
AU - Ma, Buyong
AU - Nussinov, Ruth
AU - Chen, Xinbin
N1 - Funding Information:
The authors would like to thank Chrisoula Toupadakis Skouritakis for creating the graphic working model. All simulations reported in this work were performed using the high-performance computational facilities at the NIH Biowulf supercomputer. This project was funded in whole or in part with federal funds from the NCI, NIH, under contract HHSN261200800001E. This research was also supported (in part) by the Intramural Research Program of NIH, NCI, Center for Cancer Research (RO1 CA250338, RO1 CA195828, and T32 CA108459).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-20-3157
DO - 10.1158/0008-5472.CAN-20-3157
M3 - Article
C2 - 33472892
AN - SCOPUS:85104822215
VL - 81
SP - 1827
EP - 1839
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 7
ER -