4,5-Dimethoxycanthin-6-one is a novel LSD1 inhibitor that inhibits proliferation of glioblastoma cells and induces apoptosis and pyroptosis

Wei Li,Yuan-Yuan Xiong,Bai-Sheng Huang,Li-Jian Yang,Li-Xiang Wu

doi:10.1186/s12935-021-02434-5

Abstract

BackgroundGlioblastoma is one of the most common fatal intracranial malignancies. Lysine-specific demethylase 1 (LSD1) reportedly has therapeutic effects on a variety of tumors. This study explored the therapeutic effect of LSD1 inhibition on glioblastoma cell lines and the possible underlying mechanisms.MethodsThe MTT assay was utilized to screen for the sensitivity of U87, U251 and T98G cells to 4, 5-dimethoxycarrageenin-6-one. qRT-PCR and western blot were used to measure the proliferation, apoptosis, and pyroptosis signaling pathway expression to observe the effect of LSD1 inhibition on U251 and T98G cells. Flow cytometry, immunofluorescence, immunohistochemistry, wound scratch, clone formation, and TUNEL assay were used to analyze the effects of 4, 5-dimethoxycanthin-6-one on glioblastoma cells. The effect of 4, 5-dimethoxycanthin-6-one was examined in vivo in BALB/c nude mice injected with U251 cells. HE staining was used to detect the histopathology of the tumor.ResultsLSD1 specifically catalyzes the demethylation of monomethylated and demethylated histone H3 lysine at position 4 (h3k4me1, h3k4me2, h3k4me3) and lysine at position 9 (h3k9me1). This regulated the transcriptional activity of proliferation, apoptosis, and pyroptosis signaling pathway genes. In vitro, the proliferation of glioblastoma cells was decreased in the 4, 5-dimethoxycanthin-6-one group. The expression of Caspase1 in glioblastoma cells treated with 4, 5-dimethoxycanthin-6-one increased, and the number of apoptotic cells increased. The tumor volume of mice injected with 4, 5-dimethoxycanthin-6-one decreased significantly.Conclusion4, 5-Dimethoxycanthin-6-one could act as a novel inhibitor of LSD1 to regulate glioblastoma, which could inhibit the proliferation of U251 and T98G cells and induce their apoptosis and pyroptosis. It is a potential drug for the treatment of glioblastoma.

Highlights

Glioblastoma is one of the most aggressive cancers of the central nervous system
Enrichment effect of 4, 5‐dimethoxycanthin‐6‐one on methylated H3 peptide substrate in glioblastoma cells Based on the anti-Lysine-specific demethylase 1 (LSD1) activity of 4, 5-dimethoxycanthin-6-one, we studied the effect of its accumulation on methylated H3 peptide substrates in glioblastoma cells
4, 5‐Dimethoxycanthin‐6‐one is a novel LSD1 inhibitor that inhibits the AKT/mammalian target of rapamycin (mTOR) and MAPKsignaling pathways in glioblastoma cells we explored whether the proliferation of glioblastoma cells was affected

Summary

Introduction

Glioblastoma is one of the most aggressive cancers of the central nervous system. Glioblastoma has a poor prognosis [1] with a median survival time of 5–15 months [2]. Frequent change targeting in glioblastoma cells, such as mammalian target protein phosphoinositide 3-kinase/protein kinase B/rapamycin (PI3K/AKT/mTOR), p53 and retinoblastoma (RB) pathways, epidermal growth factor receptor genes, and amplification or mutation failure can improve the prognosis. This may be due to the redundancy of the compensation mechanism and the insufficient coverage of some targets related to the blood–brain barrier or poor tolerance and safety [6]. Methylation of histone 3 lysine 4 (H3K4) residues is associated with increased gene expression and is reduced in severe glioblastoma cases [7]. This study explored the therapeutic effect of LSD1 inhibition on glioblastoma cell lines and the possible underlying mechanisms

Methods

Results

Conclusion