Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Minuesa, Gerard; Albanese, Steven K.; Chow, Arthur; Schurer, Alexandra; Park, Sun-Mi; Rotsides, Christina Z.; Taggart, James; Rizzi, Andrea; Naden, Levi N.; Chou, Timothy; Gourkanti, Saroj; Cappel, Daniel; Passarelli, Maria C.; Fairchild, Lauren; Adura, Carolina; Glickman, J. Fraser; Schulman, Jessica; Famulare, Christopher; Patel, Minal; Eibl, Joseph K.; Ross, Gregory M.; Tan, Derek S.; Leslie, Christina; Beuming, Thijs; Goldgur, Yehuda; Chodera, John D.; Kharas, Michael G.

doi:10.1101/321174

Cited by 18 publications

(33 citation statements)

References 83 publications

(99 reference statements)

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“…Upregulation of MSI2 variant 2 was observed in a large number of cancers by TCGA RNA-seq data sets [45]. Meanwhile, the small-molecule targeting of MSI2 activity is used in murine AML leukemia model [46]. The potential role of MSI2 isoforms and their small-molecule targets in PC will be further investigated in our future study.…”

Section: Resultsmentioning

confidence: 99%

Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling

Sheng

Shi

Lin

et al. 2020

J Exp Clin Cancer Res

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Background: Our previous study showed Musashi2 (MSI2) promoted chemotherapy resistance and pernicious biology of pancreatic cancer (PC) by down-regulating Numb and p53. We further explored the novel molecular mechanism involving its oncogenic role in PC development. Methods: We investigated the potential role and mechanism of MSI2 in EGF-induced EMT in PC in vitro and vivo. Results: EGF enhanced EGFR (epidermal growth factor receptor) phosphorylation, induced EMT and activated ZEB1-ERK/MAPK signaling in 2 PC cells. However, MSI2 silencing reversed EGF stimulated function, including inhibiting EGF-promoted EMT-like cell morphology and EGF-enhanced cell invasion and migration. Meanwhile, MSI2 silencing inhibited EGF-enhanced EGFR phosphorylation at tyrosine 1068 and reversed EGF-induced change of the key proteins in EMT and ZEB1-ERK/MAPK signaling (ZEB1, E-cad, ZO-1, β-catenin, pERK and c-Myc). Additionally, MSI2 was co-stained and co-immunoprecipitated with ZEB1, pERK and c-Myc in PC cells by IF and co-IP, implying a close interaction between them. In vivo, MSI2 silencing inhibited pancreatic tumor size in situ and distant liver metastases. A close relationship of MSI2 with EMT and ZEB1-ERK/MAPK signaling were also observed in vivo and human PC samples, which coordinately promoted the poor prognosis of PC patients. Conclusions: MSI2 promotes EGF-induced EMT in PC via ZEB1-ERK/MAPK signaling.

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Section: Resultsmentioning

confidence: 99%

Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling

Sheng

Shi

Lin

et al. 2020

J Exp Clin Cancer Res

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“…During the review of this manuscript, a crystal structure of a MSI2‐RRM1 construct spanning K22‐K104 was released. The structure is similar overall to the structure reported here and superposition of the new release and our structure yielded an RMSD of 1.11 Å between Cα atoms (78 residues).…”

Section: Resultsmentioning

confidence: 99%

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

et al. 2019

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Musashi‐2 (MSI2) belongs to Musashi family of RNA binding proteins (RBP). Like Musashi‐1 (MSI1), it is overexpressed in a variety of cancers and is a promising therapeutic target. Both MSI proteins contain two N‐terminal RNA recognition motifs and play roles in posttranscriptional regulation of target mRNAs. Previously, we have identified several inhibitors of MSI1, all of which bind to MSI2 as well. In order to design MSI2‐specific inhibitors and compare the differences of binding mode of the inhibitors, we set out to solve the structure of MSI2‐RRM1, the key motif that is responsible for the binding. Here, we report the crystal structure and the first NMR solution structure of MSI2‐RRM1, and compare these to the structures of MSI1‐RBD1 and other RBPs. A high degree of structural similarity was observed between the crystal and solution NMR structures. MSI2‐RRM1 shows a highly similar overall folding topology to MSI1‐RBD1 and other RBPs. The structural information of MSI2‐RRM1 will be helpful for understanding MSI2‐RNA interaction and for guiding rational drug design of MSI2‐specific inhibitors.

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“…Other mechanisms in addition to the β-catenin ubiquitination and degradation might account for the decrease in Wnt/Notch signaling we observed in DLD-1 cells. In the future, we will carry our further target validation studies and examination of other MSI targets including but not limited to SMAD3 and TGFβR1 [ 29 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction

Lan

Liu

Xing

et al. 2020

Cancers

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RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb, APC, and P21WAF-1, key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1–mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from Aspergillus nidulans. One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology.

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Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Abstract: SUMMARY 37The MUSASHI family of RNA binding proteins (MSI1 and MSI2)

Cited by 18 publications

References 83 publications

Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling

Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK/MAPK signaling

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction

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