Research ArticleExperimental Studies
Open Access

Y-box Binding Protein 1 as a Target Molecule of a Novel Coumarin-based Anti-metastatic Agent

EISHI ASHIHARA, YUKI SUGIYAMA, KEIGO KAWASHIMA, RENA KAWASHIMA, YUKI TODA, SHIGEKUNI HOSOGI, MASATO YOSHIZAWA and YASUNAO HATTORI
Anticancer Research June 2026, 46 (6) 3023-3031; DOI: https://doi.org/10.21873/anticanres.18177

Abstract

Background/Aim: We previously demonstrated that a novel coumarin-based compound, 7,8-dihydroxy-3-(4′-hydroxyphenyl)coumarin (DHC), suppresses metastasis of LM8 osteosarcoma cells both in vitro and in vivo. However, the molecular target of DHC remains unclear. The aim of this study was to develop novel DHC-derived compounds and to identify their target molecule.

Materials and Methods: Novel coumarin-based compounds were designed and evaluated for their effects on LM8 osteosarcoma cell invasion and migration. To identify a candidate target molecule of the newly synthesized compound SSKP-0076, liquid chromatography–mass spectrometry analysis was performed. The identified candidate molecule was further validated using RNA interference.

Results: Three novel coumarin-based compounds, SSKP-0076, SSKP-0081, and SSKP-0082, were synthesized. All compounds significantly inhibited invasion and migration of LM8 cells. Liquid chromatography–mass spectrometry combined with Mascot database searching identified Y-box binding protein 1 (Ybx1) as a candidate target molecule of SSKP-0076. Knockdown of Ybx1 by specific siRNAs significantly suppressed invasion and migration of LM8 cells and reduced the protein expression of the small GTP-binding proteins RhoA and Rac1, without affecting their mRNA expression levels. These effects were consistent with those observed following DHC treatment.

Conclusion: Ybx1 is a potential target molecule of the novel anti-metastatic coumarin-based compound SSKP-0076.

Keywords:

Introduction

Cancer metastasis is a well-known life-limiting factor. Despite advances in the fields of medicine and pharmacy, no agents that effectively prevent cancer metastases have not been emerged; therefore, development of anti-metastatic agents remains an unmet medical need. Recently, we demonstrated that 7,8-dihydroxy-3-(4′-hydroxyphenyl)coumarin (DHC) suppresses the migration and invasion of mouse osteosarcoma LM8 cells, as well as inhibiting spontaneous metastases and prolonging survival in a LM8-bearing mouse model. In addition, we showed that DHC increases degradation of small GTP-binding proteins including RhoA and Rac1 (both of which regulate actin reorganization), thereby decreasing formation of intracellular actin filaments (1); however, the molecule targeted by DHC has not been identified.

Y-box binding protein 1 (Ybx1), a member of the cold shock domain-containing protein family, is a multifunctional protein overexpressed in various cancer tissues, as well as an oncoprotein involved in cancer growth, stemness, and metastasis (2, 3). Ybx1 binds to both DNA and RNA, and functions as a transcription and translation factor for various proteins. The protein is overexpressed by various human cancers and is related to a poor prognosis for cancer patients. Overexpression of Ybx1 is associated with metastasis and invasion of colorectal cancer; indeed, suppression of Ybx1 by dactolisib (BEZ235), a phosphatidylinositol 3-kinase/mTOR inhibitor, reduces proliferation and motility of colorectal cancer cells (4). Silencing the Ybx1 gene inhibits proliferation and migration of multiple types of cancer cells, including triple-negative breast cancer (5), pancreatic cancer (6), and colorectal cancer (7); therefore, Ybx1 is a potential cancer biomarker and therapeutic target.

In the present study, we synthesized novel compounds derived from DHC. We next investigated their effects on cell invasion and migration as well as their target molecule. We demonstrated that Ybx1 is a candidate target molecule of a novel coumarin-based anti-metastatic agent, SSKP-0076.

Materials and Methods

Cell culture. The LM8 mouse osteosarcoma cell line (8) was kindly provided by K. Itoh (Nozaki Tokushukai Hospital, Daito, Japan). The LM8 cells were cultured in high-glucose Dulbecco’s modified Eagle’s medium (DMEM; Nacalai Tesque, Kyoto, Japan) containing 10% heat-inactivated fetal bovine serum (FBS; Thermo Fisher Scientific, Waltham, MA, USA) and 1% penicillin-streptomycin (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), and maintained in a fully humidified atmosphere (20% O2, 5% CO2, and 75% N2) and regularly tested negative for Mycoplasma infection using the Venor®GeM Classic Mycoplasma Detection Kit (Minerva Biolabs, Berlin, Germany).

Synthesis of the coumarin-based compounds. To a solution of salicylaldehyde derivative in CH2Cl2 were added a phenyl acetic acid derivative (1.5 eq.), 4-dimethylaminopiridine (5.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.0 eq.), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.5 eq.). The mixture was then stirred for 24 h at 40 °C under Ar, after which the reaction was quenched with addition of diluted aqueous HCl. The mixture was then subjected to extraction using CHCl3. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in CH2Cl2, followed by addition of BBr3 (6.0 eq., 1 M solution in CH2Cl2) at 0 °C. The mixture was then stirred for 24 h at room temperature under Ar, after which the reaction was quenched with methanol. The mixture was filtered, and the filtrate was concentrated prior to use (without purification) in the next step. Finally, the residue was dissolved in methanol, followed by addition of Pd-C (10 wt%) under Ar. This mixture was stirred for 20 h at room temperature under H2, followed by filtration and concentration to yield the SSKP compound [SSKP-42: 1H NMR (DMSO-d6, 500 MHz) δ 10.19 (1H, s), 8.84 (1H, s), 8.83 (1H, s), 7.95 (1H, s), 7.17-7.13 (2H, m), 7.10-7.06 (1H, m), 6.71 (1H, d, J=8.7 Hz), 6.69 (1H, d, J=3.0 Hz), 6.63 (1H, dd, J=8.6, 3.0 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 159.6, 149.7, 147.7, 144.6, 142.6, 141.9, 125.9, 124.7, 122.7, 120.5, 118.6, 118.0, 117.2, 116.7, 116.5; SSKP-76; 1H NMR (DMSO-d6, 300 MHz) δ 8.81 (2H, brs), 7.86 (1H, s), 7.04 (1H, t, J=7.7 Hz), 6.90 (1H, dd, J=8.0, 1.5 Hz), 6.86 (1H, dd, J=7.6, 1.5 Hz), 6.71-6.60 (3H, m), 5.39 (2H, brs); 13C NMR (DMSO-d6, 75 MHz) δ 159.6, 149.6, 147.7, 143.0, 140.4, 136.1, 125.4, 124.6, 122.9, 119.4, 117.2, 116.6, 116.3, 116.1, 115.1; SSKP-81: 1H NMR (DMSO-d6, 300 MHz) δ 8.61 (2H, brs), 7.69 (1H, s), 7.28 (1H, d, J=8.4 Hz), 6.79 (1H, dd, J=8.8, 2.6 Hz), 6.71-6.55 (5H, m), 5.69 (1H, brs); 13C NMR (DMSO-d6, 75 MHz) δ 160.5, 155.8, 153.0, 149.6, 147.6, 143.2, 129.5, 123.5, 117.9, 117.4, 116.5, 115.6, 111.7, 108.9, 98.3; SSKP-82: 1H NMR (DMSO-d6, 300 MHz) δ 8.74 (2H, d, J=7.7 Hz), 7.75 (1H, s), 7.07 (1H, d, J=8.8 Hz), 6.64-6.49 (5H, m), 6.40 (1H, s), 5.16 (1H, brs); 13C NMR (DMSO-d6, 75 MHz) δ 160.1, 149.6, 147.7, 145.7, 145.0, 142.3, 125.7, 123.1, 119.9, 118.6, 117.3, 116.6, 116.4, 116.2, 110.3 ppm].

Cell proliferation assay. The proliferation of LM8 cells was evaluated via a WST-8 assay as described previously (1, 9). In brief, LM8 cells were seeded into each well of a flat-bottomed 96-well plate (Thermo Fisher Scientific) and treated with serial dilutions of the compounds for 72 h. After treatment with Cell Counting Kit-8 reagent (Dojindo Laboratories, Kumamoto, Japan) for 3 h, absorbance was measured using a microplate reader (GloMax, Promega, Madison, WI, USA).

Cell invasion and migration assays. The effects of compounds or small interfering RNAs (siRNAs) on cell invasion and migration were evaluated using a previously described assay (1, 10). When we examined the effects of the compounds, LM8 cells were seeded at 3.0×104 cells/ml in cell culture inserts containing 8 μm diameter pores (BD Biosciences, Franklin Lakes, NJ, USA) and treated with the compounds at the concentrations of 3 and 30 μM. When we investigated the effects of siRNAs, siRNAs were treated at a concentration of 5 nM at a 6-well plate (Thermo Fischer Scientific) for 72 h. We then collected the siRNA-treated cells, and the cells were seeded at 3.0×104 cells/ml in cell culture inserts containing 8 μm diameter pores (BD Biosciences). Inserts coated with Matrigel Basement Membrane Matrix (BD Biosciences) were used for invasion assays, whereas non-coated inserts were used for migration assays. The inserts were placed in 24-well companion plates (BD Biosciences) with DMEM containing 1% FBS as a chemoattractant. After 24 h of incubation, the Matrigel and non-invading and migrating cells in the upper chamber were removed with a cotton swab. Cells on the bottom of the chamber were fixed with 100% methanol and stained with Giemsa solution (FUJIFILM Wako Pure Chemical Corporation). Images of cells in three randomly chosen fields (40× magnification) per insert were acquired under a light microscope (BX50, Olympus, Tokyo, Japan) equipped with a DP72 digital camera (Olympus). Migrated and invaded cells in these images were counted using the automatic cell counting system (10).

Identification of candidate for target molecule. SSKP-0076 was bound to FG beads (TAMAGAWA SEIKI, Nagano, Japan) and then mixed the beads with the LM8 cell lysate and eluted the proteins. The eluate was then electrophoresed in a 7.5-15% sodium dodecyl sulfate (SDS)-polyacrylamide gel (DRC, Tokyo, Japan), which was then stained using a Silver Stain MS Kit (FUJIFILM Wako Pure Chemical Corporation). These steps were performed according to the manufacturer’s instructions. The bound proteins were isolated, digested, and analyzed using a liquid chromatography-mass spectrometry, and then subjected to a Mascot search (11) and identified Ybx1 as a candidate target molecule.

Knockdown of Ybx-1 using small interfering RNAs (siRNAs). SiRNAs targeting Ybx-1 (s76162; si_Ybx1_#1, s76163; si_Ybx1_#2) and a negative control siRNA (product number, 4390846; si_control) were purchased from Thermo Fischer Scientific. LM8 cells were seeded at 2.0×104 cells in 3 ml of medium into each well of the 6-well plate (Thermo Fisher Scientific) and transfected with 5 nM of each siRNA in Opti-MEM (Thermo Fisher Scientific) containing lipofectamine RNAiMAX (Thermo Fisher Scientific). The following sequences of siRNAs were used: si_Ybx1_#1 (s76162), GCAAUGAAGAGGACAAAGAtt (Sence) and UCUUUGUCCUCUUCAUUGCca (Antisence); si_Ybx1_#2 (s76163), CCAGCAAAAUUACCAGAAUtt (Sence) and AUUCUGGUAAUUUUGCUGGta (Antisence).

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). LM8 cells were seeded at 2.0×104 cells in 3 ml of medium into each well of a 6-well plate and treated with si_control, si_Ybx1_#1, and si_Ybx1_#2 (5 nM each) for 72 h. RNA was purified using the NucleoSpin RNA kit (Takara Bio Inc., Kusatsu, Japan) and subjected to reverse transcription using the ReverTra Ace® qPCR RT kit (TOYOBO CO., LTD., Osaka, Japan) to produce cDNA. The mouse Ybx-1, RhoA, Rac1, and Gapdh mRNA expression levels were measured by real-time PCR using Brilliant III Ultra-Fast SYBR Green QPCR Master Mix (Agilent Technologies, Santa Clara, CA, USA) and the Thermal Cycler Dice Real Time System II (Takara Bio Inc.). The following gene-specific primers were used: Ybx-1, 5′-GGACAAGAAGGTCATCGCAAC-3′ and 5′-AGTCTCTCCATCGCCTACACT-3′; RhoA, 5′-ACCTGTGTGTTTTCAGCACCT-3′ and 5′-CCATCACCAACAATCACCAG-3′; Rac1, 5′-AGATGCAGGCCATCAAGTGT-3′ and 5′-GAGCAGGCAGGTTTTACCAA-3′; Gapdh, 5′-TGCACCACCAACTGCTTAG-3′ and 5′-GATGCAGGGATGATGTTC-3′.

Western blotting. Protein levels were examined using western blotting. LM8 cells were seeded at 2.0×104 cells in 3 ml of medium into each well of the 6-well plate (Thermo Fisher Scientific) and treated with si_control, si_Ybx1_#1, or si_Ybx1_#2 (5 nM each) for 72 h. Cells were then treated as described previously (10, 12). We performed the western blot analysis with three independent biological replicates, each containing one technical replicate. samples (containing 20 μg of protein) were first separated by SDS-polyacrylamide gel electrophoresis and blotted with primary antibodies specific for the following proteins: Ybx1 [ab76149 (EP2708Y), Abcam, Cambridge, UK], RhoA (sc-419, Santa Cruz Biotechnology, Dallas, TX, USA), Rac1 (66122-1-Ig, Proteintech Japan, Tokyo, Japan), and Gapdh (#2118, Cell Signaling Technology, Danvers, MA, USA). Horseradish peroxidase-coupled anti-rabbit and anti-mouse IgG (Cell Signaling Technology) were used as secondary antibodies. Immunoreactive proteins were detected using ECL or ECL Prime Western Blotting Detection kits (GE Healthcare, Chicago, IL, USA).

Statistical analysis. Analyses were performed using GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA, USA). Multiple comparisons were performed using one-way ANOVA Bonferroni’s multiple comparison test. A p-value of 0.05 was considered statistically significant.

Results

Effects of synthetic coumarin compounds on invasion and migration of LM8 cells. First, we designed and synthesized SSKP-0042 (Figure 1), a derivative of DHC (1), and confirmed that it inhibited invasion and migration of LM8 cells more effectively than DHC (data not shown). We then designed SSKP-0076, -0081, and -0082 to investigate the target molecule (Figure 1).

Figure 1.
Figure 1.

Structures of SSKP-0076, -0081, and -0082. Coumarin-based SSKP-0076, -0081, and -0082 compounds were based on 7,8-dihydroxy-3-(4′-Hydroxyphenyl)coumarin (DHC) and developed via SSKP-0042.

The concept underlying the development of anti-metastatic agents is direct suppression of cell invasion and migration. To achieve this, we performed a WST-8 assay to identify the maximum concentration of each compound that did not affect cell proliferation. The results showed that the compounds did not inhibit cell proliferation at concentrations up to 30 μM (Figure 2A). Next, we investigated the inhibitory effects of the compounds on cell invasion and migration at the concentrations of 3 and 30 μM. LM8 cells were treated with each compound for 24 h, and cells that had invaded and migrated cells were counted. All three compounds suppressed invasion and migration of LM8 cells significantly, with both being suppressed almost completely at 30 μM (Figure 2B). DHC-derived SSKP compounds could be seed compounds for anti-metastatic agents.

Figure 2.
Figure 2.

Effects of SSKP-0076, -0081, and -0082 on invasion and migration of LM8 cells. (A) Effects of novel coumarin-based compounds SSKP-0076, -0081, and -0082 on the proliferation of LM8 osteosarcoma cells. Cell proliferation was evaluated after treatment (for 72 h) with each of the compounds. Data for each compound are presented as the meanstandard deviation (n=4). (B) The inhibitory effects of each compound on cell invasion and migration. LM8 cells were treated for 24 h with each compound at the indicated concentrations. Data are presented the mean±standard deviation (n=10). Data were analyzed using one-way ANOVA, and multiple comparisons of means were performed using Bonferroni’s correction. p<0.05 was considered significant. **p<0.01. Data are representative data of three or four independent experiments, each with similar results.

Validation of Ybx1 as a target molecule for SSKP-0076. Next, we investigated the molecule targeted by these compounds. We obtained the eluted cell lysate using SSKP-0076 bound to FG beads. After electrophoreses in the SDS-polyacrylamide gel, the bound proteins were analyzed using a liquid chromatography-mass spectrometry and then subjected to a Mascot search. We then nominated Ybx1 as a target molecule of SSKP-0076. To validate Ybx1 as a target molecule for SSKP-0076, western blotting analyses using of both heat- and salt-eluted solutions were conducted and showed that Y-box binding protein 1 was detected at approximately 50 kDa (Figure 3A). The anti-YB1 antibody used in this study recognizes Ybx1 at approximately 50 kDa (https://doc.abcam.com/datasheets/active/ab76149/en-jp/yb1-antibody-ep2708y-ab76149.pdf). Accordingly, we confirmed that SSKP-0076 bound to Ybx1. Next, we conducted RNA interference assays to investigate whether targeting of Ybx1 by SSKP-0076 prevents cell invasion and migration using RNA interference. After confirming generation of siRNAs specific for Ybx1 (Figure 3B and C), we investigated their inhibitory effects of siRNAs on the cell invasion and migration. Both Ybx1 siRNA #1 and #2 significantly suppressed invasion and migration of LM8 cells significantly (Figure 4). Consistent with the effects of our previous compound DHC (1), treatment with siRNAs reduced expression of small GTP-binding proteins RhoA and Rac1 (Figure 3B) but had no effect on the levels of their respective mRNA transcripts (Figure 3C). Taken together, these data confirm Ybx1 as a target molecule of the coumarin-based compound SSKP-0076.

Figure 3.
Figure 3.

Validation of Y-box binding protein 1 as a target molecule of SSKP-0076. (A) Detection of Y-box binding protein 1 in the eluted cell lysate and in the whole cell lysate. After the cell lysate was mixed with FG beads bound to SSKP-0076, western blot analysis of the eluted protein solutions was conducted. Y-box binding protein 1 was detected at approximately 50 kDa (arrow). (B) Changes in protein expression levels of Y-box protein 1, as well as RhoA and Rac1 proteins, after treatment for 72 h with siRNAs targeting Y-box binding protein 1. GAPDH was used as an internal control. Data are representative data of three independent experiments. (C) Changes in expression of mRNA transcripts of Y-box protein 1, RhoA, and Rac1 proteins after treatment with siRNAs targeting Y-box binding protein 1; mRNA transcript levels after a 72 h-treatment with siRNAs were examined by reverse transcription-quantitative polymerase chain reaction. Data are presented as the mean±standard error of the mean of three independent experiments. Gapdh was used as an internal control. Data were analyzed using one-way ANOVA and multiple comparisons of means were performed using Bonferroni’s correction. p<0.05 was considered significant. ****p<0.001. ns: Not significant; Ybx1, Y-box binding protein 1; si_control, scramble control siRNA; si_Ybx1, siRNA targeting Y-box binding protein 1; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; RhoA, Ras homolog family member A; Rac1, Ras-related C3 botulinum toxin substrate 1.

Figure 4.
Figure 4.

Effects of siRNAs targeting Y-box binding protein 1 on invasion and migration of LM8 cells. The inhibitory effects of the siRNAs were evaluated. Data are presented as the mean±standard error of the mean of three independent experiments. Data were analyzed using one-way ANOVA and multiple comparisons of means were performed using Bonferroni’s correction. p<0.05 was considered significant. *p<0.05, **p<0.01. Ybx1, Y-box binding protein 1; si_control, scramble control siRNA; si_Ybx1, siRNA targeting Y-box binding protein 1.

Discussion

Coumarin and its derivatives exhibit a wide range of pharmacological activities, including tryglyceride-lowering effects (13), inhibition of monoamine oxidase (14), attenuation of Aβ protein accumulation in an Alzheimer’s disease mouse model (15), and anti-proliferative effects on cancer cells (16). We previously demonstrated that a DHC-based compound exerts anti-metastatic effects by suppressing invasion and migration of LM8 osteosarcoma cells through degradation of the small GTP-binding proteins RhoA and Rac1 (1). In the present study, we synthesized novel DHC-based compounds and identified Ybx1 as a target of the coumarin-derived anti-metastatic agent SSKP-0076 using mass spectrometry.

Ybx1 is a well-established oncoprotein. Previous studies have identified Ybx1 as a therapeutic target in several cancers using small molecules and siRNAs (4-7). However, to our knowledge, Ybx1 has not previously been reported as a target of coumarin-based compounds. To validate Ybx1 as a functional target of SSKP-0076, we established LM8 cells with reduced Ybx1 expression using RNA interference. Ybx1 knockdown significantly suppressed invasion and migration. In addition, siRNA-mediated knockdown of Ybx1 reduced RhoA and Rac1 protein levels without affecting their mRNA expression. These findings demonstrate that inhibition of Ybx1 promotes degradation of RhoA and Rac1 proteins, consistent with our previous findings for DHC (1), and indicate that SSKP-0076 may suppress metastasis in osteosarcoma.

Study limitations. First, the precise mechanism by which Ybx1 regulates RhoA and Rac1 protein stability remains to be elucidated. Second, the binding mode of SSKP-0076 to Ybx1 has not been determined, as neither molecular docking (17) nor X-ray crystallographic analysis has been performed. Further studies are required to clarify these issues and to define the structural basis of this interaction. In addition, the anti-metastatic efficacy of SSKP-0076 should be validated in clinical settings.

Conclusion

We demonstrated that the DHC-derived compound SSKP-0076 interacts with Ybx1, and that Ybx1 knockdown suppresses invasion and migration of LM8 cells through downregulation of RhoA and Rac1 protein expression, consistent with DHC treatment. These findings suggest Ybx1 as a novel molecular target of the anti-metastatic agent SSKP-0076 and support its potential as a therapeutic strategy for osteosarcoma.

Acknowledgements

The Authors thank an honorary Professor Masayuki Yamashita (Laboratory of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan) for synthesizing the coumarin compounds.

Footnotes

  • Authors’ Contributions

    Eishi Ashihara: Conceptualization, methodology, project administration, funding administration, supervision, writing – review and editing. Yuki Sugiyama: Methodology and investigation. Keigo Kawashima: Methodology and investigation. Rena Kawashima: Methodology and investigation. Yuki Toda: Methodology and investigation. Shigekuni Hosogi: Methodology and investigation. Masato Yoshizawa: Methodology, supervision, review, and editing. Yasunao Hattori: Conceptualization, methodology, investigation, supervision, writing – review and editing.

  • Conflicts of Interest

    The Authors declare no conflicts of interest to disclose in relation to this study.

  • Funding

    This work was supported by AMED under Grant Numbers 22ym0126810j0001 and 23ym0126810j0002.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received February 21, 2026.
  • Revision received March 29, 2026.
  • Accepted April 6, 2026.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Y-box Binding Protein 1 as a Target Molecule of a Novel Coumarin-based Anti-metastatic Agent
EISHI ASHIHARA, YUKI SUGIYAMA, KEIGO KAWASHIMA, RENA KAWASHIMA, YUKI TODA, SHIGEKUNI HOSOGI, MASATO YOSHIZAWA, YASUNAO HATTORI
Anticancer Research Jun 2026, 46 (6) 3023-3031; DOI: 10.21873/anticanres.18177
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