Histone methyltransferase SMYD2 selective inhibitor LLY-507 in combination with poly ADP ribose polymerase inhibitor has therapeutic potential against high-grade serous ovarian carcinomas

Kukita, Asako; Sone, Kenbun; Oda, Katsutoshi; Hamamoto, Ryuji; Kaneko, Syuzo; Komatsu, Masaaki; Wada, Miku; Honjoh, Harunori; Kawata, Yoshimasa; Kojima, Masahiro; Oki, Sadaaki; Sato, Masakazu; Asada, Kenichi; Taguchi, Ayumi; Miyasaka, Aki; Nagasaka, Kazunori; Matsumoto, Yōko; Wada‐Hiraike, Osamu; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.1016/j.bbrc.2019.03.155

Cited by 26 publications

(32 citation statements)

References 20 publications

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“…In the field of gynecologic cancer, an association between poor prognosis of cervical cancer and SMYD2 upregulation has been reported (29). Additionally, our previous study indicated that SMYD2 knockdown could suppress HGSOC cell proliferation and induce apoptosis (18). The findings of the present study are consistent with these previous reports.…”

Section: Discussionsupporting

confidence: 92%

“…A previous study has indicated that LLY-507 induces apoptosis and suppresses HGSOC cell proliferation (18). Moreover, SMYD2 inhibitors have a long-term inhibitory effect on the proliferation of HGSOC cells in colony-formation assays (18).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study suggested that SMYD2 was upregulated in clinical samples of high-grade serous ovarian cancer (HGSOC); additionally, SMYD2 suppression induced apoptosis in HGSOC cells (18). However, the role of SMYD2 in OCCC remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells

et al. 2020

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Previous studies have suggested that histone methylation can modulate carcinogenesis and cancer progression. For instance, the histone methyltransferase SET and MYND domain containing 2 (SMYD2) is overexpressed in several types of cancer tissue. The aim of the present study was to determine whether SMYD2 could serve a therapeutic role in ovarian clear cell carcinoma (OCCC). Reverse transcription-quantitative PCR was used to examine SMYD2 expression in 23 clinical OCCC specimens. Moreover, OCCC cell proliferation and cell cycle progression were also examined following small interfering RNA-mediated SMYD2 silencing or treatment with a selective SMYD2 inhibitor. SMYD2 was significantly upregulated in clinical OCCC specimens, compared with normal ovarian tissue. In addition, SMYD2 knockdown decreased cell viability as determined via a Cell Counting Kit-8 assay. Moreover, the proportion of cells in the sub-G 1 phase increased following SMYD2 knockdown, suggesting increased apoptosis. Treatment with the SMYD2 inhibitor LLY-507 suppressed OCCC cell viability. These results suggested that SMYD2 could promote OCCC viability, and that SMYD2 inhibition induced apoptosis in these cells. Thus, SMYD2 inhibitors may represent a promising molecular targeted approach for OCCC treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells

et al. 2020

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“…Similar to our expression profile, high levels of SMYD2 expression has been associated with unfavorable prognosis in different cancer types, such as breast cancer (mRNA expression) and cervical cancer (protein expression) (33,34). A recent study reported overexpression of SMYD2 in cancer vs. normal tissue, and associated higher expression of SMYD2 with enhanced proliferation in HGSC (35). NUP155-positivity correlated with shorter OS in CCC, while esophageal squamous cell carcinoma showed an association between low expression of NUP155 with shorter OS (36).…”

Section: Discussionsupporting

confidence: 84%

Validation of Novel Prognostic Biomarkers for Early-Stage Clear-Cell, Endometrioid and Mucinous Ovarian Carcinomas Using Immunohistochemistry

et al. 2020

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Early-stage (I and II) ovarian carcinoma patients generally have good prognosis. Yet, some patients die earlier than expected. Thus, it is important to stratify early-stage patients into risk groups to identify those in need of more aggressive treatment regimens. The prognostic value of 29 histotype-specific biomarkers identified using RNA sequencing was evaluated for early-stage clear-cell (CCC), endometrioid (EC) and mucinous (MC) ovarian carcinomas (n = 112) using immunohistochemistry on tissue microarrays. Biomarkers with prognostic significance were further evaluated in an external ovarian carcinoma data set using the web-based Kaplan-Meier plotter tool. Here, we provide evidence of aberrant protein expression patterns and prognostic significance of 17 novel histotype-specific prognostic biomarkers [10 for CCC (ARPC2, CCT5, GNB1, KCTD10, NUP155, RPL13A, RPL37, SETD3, SMYD2, TRIO), three for EC (CECR1, KIF26B, PIK3CA), and four for MC (CHEK1, FOXM1, KIF23, PARPBP)], suggesting biological heterogeneity within the histotypes. Combined predictive models comprising the protein expression status of the validated CCC, EC and MC biomarkers together with established clinical markers (age, stage, CA125, ploidy) improved the predictive power in comparison with models containing established clinical markers alone, further strengthening the importance of the biomarkers in ovarian carcinoma. Further, even improved predictive powers were demonstrated when combining these models with our previously identified prognostic biomarkers PITHD1 (CCC) and GPR158 (MC). Moreover, the proteins demonstrated improved risk prediction of CCC-, EC-, and MC-associated ovarian carcinoma survival. The novel histotype-specific prognostic biomarkers may not only improve prognostication and patient stratification of early-stage ovarian carcinomas, but may also guide future clinical therapy decisions.

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“…Consistent with the above conclusion, we found that these inhibitors displayed a synergistic effect with Olaparib and Niraparib in HCT-15 cells ( Figure 1A). As reported [30][31][32][33], we also observed that Olaparib and Niraparib showed a synergistic effect in combination with inhibitors of DNMT, DNA-PK, mTOR, and HDM in HCT-15 cells ( Figure 1A).…”

Section: Drug Combination Screen Identi Es Gsk3i As Acting Synergistisupporting

confidence: 82%

GSK3β Inhibition Synergizes with PARP Inhibitors through the Induction of Homologous Recombination Deficiency in Colorectal Cancer

Zhang¹,

Tian²,

Zhou³

et al. 2020

Preprint

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Background: Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in limited objective response rate (≤ 60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Methods: The effects of PARPi combined with glycogen synthase kinase 3 (GSK3) inhibitors were investigated in vitro with respect to cell viability, cell cycle and apoptosis. The synergy was assessed by calculation of the combination index (CI). GSK3α null and GSK3β null cells were generated using CRISPR/Cas9 technique. The underlying mechanism was examined by western blotting, flow cytometry, qRT-PCR and fluorescence microscopy. This combination was also evaluated in the mouse xenograft model; tumor growth and tumor lysates were analyzed, and the immunohistochemistry assay was performed. All data are presented as mean ± SD. Comparison between two groups was performed with the Student’s t-test.Result: The data showed that ~25% of oncological drugs and kinase inhibitors that were evaluated displayed synergy with PARPi in HCT-15 cells. Among the tested agents, GSK3 inhibitors (GSK3i) exhibited the strongest synergistic effect with PARPi. Moreover, the synergistic antitumor effect of GSK3 and PARP inhibition was confirmed in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. Additionally, inhibition or genetic depletion of GSK3β was found to impair HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity.Conclusion: Our results provide a mechanistic understanding of combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

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Histone methyltransferase SMYD2 selective inhibitor LLY-507 in combination with poly ADP ribose polymerase inhibitor has therapeutic potential against high-grade serous ovarian carcinomas

Cited by 26 publications

References 20 publications

The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells

The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells

Validation of Novel Prognostic Biomarkers for Early-Stage Clear-Cell, Endometrioid and Mucinous Ovarian Carcinomas Using Immunohistochemistry

GSK3β Inhibition Synergizes with PARP Inhibitors through the Induction of Homologous Recombination Deficiency in Colorectal Cancer

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