Anticancer research · 2025
Efficient Inhibition of FOXM1 Expression and Viability of High-grade Meningioma Cells by Domatinostat-mediated Dual Targeting of HDAC1 and HDAC2.
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Nakamura Kazuki, Ito Yasufumi, Nakagawa-Saito Yurika, Takenouchi Senri, Suzuki Shuhei, Togashi Keita, Sugai Asuka, Mitobe Yuta, Sonoda Yukihiko, Kitanaka Chifumi, Okada Masashi
Аннотация
BACKGROUND/AIM: High-grade meningiomas are tumors with high recurrence rates and poor prognoses, and the development of effective pharmacological therapies remains a major challenge. Forkhead box protein M1 (FOXM1), a transcription factor known to play a key role in the malignancy of high-grade meningiomas, has gained attention as a potential therapeutic target. Class I histone deacetylase (HDAC) inhibitors have been shown to suppress FOXM1 expression and cell proliferation in various cancers; however, their efficacy in high-grade meningiomas remains unclear. The present study investigated the role of class I HDACs in regulating FOXM1 expression and cell proliferation in high-grade meningioma cell lines and examined the effects of the class I HDAC inhibitor domatinostat on FOXM1 expression and cell proliferation in these cell lines.
MATERIALS AND METHODS: In high-grade meningioma cell lines, the effects of the individual or simultaneous knockdown of HDAC1 and HDAC2, as well as treatment with the class I HDAC inhibitor domatinostat, on FOXM1 mRNA expression were analyzed using a reverse transcription polymerase chain reaction (RT-PCR). The effects on FOXM1 protein expression were examined by western blot analysis. Furthermore, the impact of the knockdown of FOXM1, the individual or simultaneous knockdown of HDAC1/HDAC2, and domatinostat treatment on cell viability was evaluated using trypan blue exclusion and colony formation assays.
RESULTS: In high-grade meningioma cell lines, the knockdown of FOXM1 significantly inhibited cell proliferation. While the individual knockdown of HDAC1 or HDAC2 resulted in only limited reductions in FOXM1 expression and cell proliferation, their simultaneous knockdown markedly decreased FOXM1 expression and significantly suppressed cell proliferation. Similarly, treatment with the class I HDAC inhibitor domatinostat reduced FOXM1 expression and inhibited the proliferation of high-grade meningioma cells within a concentration range that was not toxic to normal cell lines.
CONCLUSION: Simultaneous inhibition of the class I HDACs, HDAC1 and HDAC2, reduced FOXM1 expression and suppressed cell proliferation in high-grade meningiomas. Furthermore, the class I HDAC inhibitor domatinostat inhibited FOXM1 expression and cell proliferation in high-grade meningioma cells within a concentration range that was not toxic to normal cell lines. These results suggest the potential of domatinostat as a therapeutic option for the treatment of high-grade meningiomas, which are often difficult to manage clinically.
MATERIALS AND METHODS: In high-grade meningioma cell lines, the effects of the individual or simultaneous knockdown of HDAC1 and HDAC2, as well as treatment with the class I HDAC inhibitor domatinostat, on FOXM1 mRNA expression were analyzed using a reverse transcription polymerase chain reaction (RT-PCR). The effects on FOXM1 protein expression were examined by western blot analysis. Furthermore, the impact of the knockdown of FOXM1, the individual or simultaneous knockdown of HDAC1/HDAC2, and domatinostat treatment on cell viability was evaluated using trypan blue exclusion and colony formation assays.
RESULTS: In high-grade meningioma cell lines, the knockdown of FOXM1 significantly inhibited cell proliferation. While the individual knockdown of HDAC1 or HDAC2 resulted in only limited reductions in FOXM1 expression and cell proliferation, their simultaneous knockdown markedly decreased FOXM1 expression and significantly suppressed cell proliferation. Similarly, treatment with the class I HDAC inhibitor domatinostat reduced FOXM1 expression and inhibited the proliferation of high-grade meningioma cells within a concentration range that was not toxic to normal cell lines.
CONCLUSION: Simultaneous inhibition of the class I HDACs, HDAC1 and HDAC2, reduced FOXM1 expression and suppressed cell proliferation in high-grade meningiomas. Furthermore, the class I HDAC inhibitor domatinostat inhibited FOXM1 expression and cell proliferation in high-grade meningioma cells within a concentration range that was not toxic to normal cell lines. These results suggest the potential of domatinostat as a therapeutic option for the treatment of high-grade meningiomas, which are often difficult to manage clinically.