Combination LSD1 and HOTAIR-EZH2 inhibition disrupts cell cycle processes and induces apoptosis in glioblastoma cells

Zhao, Jingjie; Jin, Weili; Yi, Kaikai; Wang, Qixue; Zhou, Junhu; Tan, Yanli; Cheng, Xu; Xiao, Menglin; Hong, Biao; Xu, Fengming; Zhang, Kailiang; Kang, Chunsheng

doi:10.1016/j.phrs.2021.105764

Cited by 36 publications

(26 citation statements)

References 45 publications

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“…Therefore, some LSD1 inhibitors have been investigated as potential antitumor drugs [ 37 ]. The expression of LSD1 increases in neuroblastoma tissues and cell lines [ 38 , 39 ], and LSD1 is related to the degree of tumor malignancy [ 40 ]. The report have described a novel dual role for the histone demethylase LSD1 in controlling cell death and innate immune responses against pHGG and DIPG cells in vitro and in vivo [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

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

Huang

Xiong

et al. 2022

Cancer Cell Int

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Background Glioblastoma 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. Methods The 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. Results LSD1 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. Conclusion 4, 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.

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Section: Discussionmentioning

confidence: 99%

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

Huang

Xiong

et al. 2022

Cancer Cell Int

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“…Similar to the aforementioned study, the current research showed that HOTAIR expression was elevated in RB cells. HOTAIR is implicated in the cell cycle process in glioblastoma [ 32 ] while silencing HOTAIR declines proliferation and promotes apoptosis of synoviocytes in osteoarthritis [ 33 ]. After delivering sh-HOTAIR into Y79 and HXO-RB44 cells with relatively high HOTAIR expression, we discovered that HOTAIR silencing repressed cell proliferation, enhanced apoptosis, and blocked the cell cycle progression of RB cells in the G0/G1 phase.…”

Section: Discussionmentioning

confidence: 99%

LncRNA HOTAIR facilitates proliferation and represses apoptosis of retinoblastoma cells through the miR-20b-5p/RRM2/PI3K/AKT axis

Zhang

2022

Orphanet J Rare Dis

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Purpose Retinoblastoma (RB) represents an adolescent eye malignancy. Long non-coding RNA (LncRNA) HOTAIR shows aberrant expression in many malignancies. This research investigated the mechanism of HOTAIR in RB. Methods Normal retinal cell lines (ARPE-19 and RPE-1) and RB cell lines (ORB50, Y79, HXO-RB44, and WERI-RB) were selected for detection of HOTAIR expression by qRT-PCR. sh-HOTAIR was delivered into Y79 and HXO-RB44 cells. Cell-cycle distribution, proliferation, and apoptosis were detected by CCK-8 assay and flow cytometry. Binding relationships among HOTAIR, miR-20b-5p, and RRM2 were confirmed using dual-luciferase assay. Roles of miR-20b-5p and RRM2 in RB cell-cycle distribution, proliferation, and apoptosis were ascertained by functional rescue experiments. Murine model of xenograft tumor was established, followed by detection of tumor growth and counting of Ki67-positive cells. Expressions of proliferation- and apoptosis-associated proteins and PI3K/AKT pathway-related proteins were determined by Western blot. Results HOTAIR was elevated in RB cells relative to that in normal retinal cells and showed relatively high expression in Y79 and HXO-RB44 cells. sh-HOTAIR induced RB cell-cycle arrest, restrained proliferation, and strengthened apoptosis. HOTAIR functioned as the ceRNA of miR-20b-5p and targeted RRM2. RB cells had poorly-expressed miR-20b-5p and highly-expressed RRM2. miR-20b-5p downregulation or RRM2 overexpression facilitated RB cell-cycle and proliferation, suppressed apoptosis, and reversed the protective effect of sh-HOTAIR on RB. sh-HOTAIR reduced tumor growth and Ki67-positive cells in vivo and inactivated PI3K/AKT pathway. Conclusion LncRNA HOTAIR upregulated RRM2 by competitively binding to miR-20b-5p and activated PI3K/AKT pathway, thereby facilitating proliferation and repressing apoptosis of RB cells.

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“…HOX transcript antisense intergenic RNA (HOTAIR) lncRNA interacting with EZH2 forms a complex with PRC2 and lysine‐specific demethylase 1 to trigger the cell cycle progression in glioblastoma cells 188 . Similarly, elevated amounts of HOTAIR in serous ovarian cancer (SOC) are associated with cell proliferation and tumor growth as well as apoptosis suppression 72 .…”

Section: Cell Cyclementioning

confidence: 99%

“…71,169 3.2.4 | HOTAIR HOX transcript antisense intergenic RNA (HOTAIR) lncRNA interacting with EZH2 forms a complex with PRC2 and lysine-specific demethylase 1 to trigger the cell cycle progression in glioblastoma cells. 188 Similarly, elevated amounts of HOTAIR in serous ovarian cancer (SOC) are associated with cell proliferation and tumor growth as well as apoptosis suppression. 72 In return, HOTAIR silencing diminishes the expression of cyclin E, the cell number in the S phase and SOC proliferation as well as enhances the number of cells in the G1/M phase.…”

Section: Hoxa11-as1mentioning

confidence: 99%

The various regulatory functions of long noncoding RNAs in apoptosis, cell cycle, and cellular senescence

Asl

Khelejani

Mahdavi

et al. 2022

J of Cellular Biochemistry

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Long noncoding RNAs (lncRNAs) are a group of noncoding cellular RNAs involved in significant biological phenomena such as differentiation, cell development, genomic imprinting, adjusting the enzymatic activity, regulating chromosome conformation, apoptosis, cell cycle, and cellular senescence. The misregulation of lncRNAs interrupting normal biological processes has been implicated in tumor formation and metastasis, resulting in cancer. Apoptosis and cell cycle, two main biological phenomena, are highly conserved and intimately coupled mechanisms. Hence, some cell cycle regulators can influence both programmed cell death and cell division. Apoptosis eliminates defective and unwanted cells, and the cell cycle enables cells to replicate themselves. The improper regulation of apoptosis and cell cycle contributes to numerous disorders such as neurodegenerative and autoimmune diseases, viral infection, anemia, and mainly cancer. Cellular senescence is a tumorsuppressing response initiated by environmental and internal stress factors. This phenomenon has recently attained more attention due to its therapeutic implications in the field of senotherapy. In this review, the regulatory roles of lncRNAs on apoptosis, cell cycle, and senescence will be discussed. First, the role of lncRNAs in mitochondrial dynamics and apoptosis is addressed. Next, the interaction between lncRNAs and caspases, pro/antiapoptotic proteins, and also EGFR/PI3K/PTEN/AKT/mTORC1 signaling pathway will be investigated. Furthermore, the effect of lncRNAs in the cell cycle is surveyed through interaction with cyclins, cdks, p21, and wnt/β-catenin/c-myc pathway. Finally, the function of essential lncRNAs in cellular senescence is mentioned.

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Combination LSD1 and HOTAIR-EZH2 inhibition disrupts cell cycle processes and induces apoptosis in glioblastoma cells

Cited by 36 publications

References 45 publications

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

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

LncRNA HOTAIR facilitates proliferation and represses apoptosis of retinoblastoma cells through the miR-20b-5p/RRM2/PI3K/AKT axis

The various regulatory functions of long noncoding RNAs in apoptosis, cell cycle, and cellular senescence

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