miR-3189 通过靶向抑制 HDAC2 抑制 GLUT3 表达抑制神经胶质瘤肿瘤发生通过调控葡萄糖代谢和增殖。
miR-3189-targeted GLUT3 repression by HDAC2 knockdown inhibits glioblastoma tumorigenesis through regulating glucose metabolism and proliferation.
机构信息
Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea.
出版信息
J Exp Clin Cancer Res. 2022 Mar 8;41(1):87. doi: 10.1186/s13046-022-02305-5.
BACKGROUND
Epigenetic regulations frequently appear in Glioblastoma (GBM) and are highly associated with metabolic alterations. Especially, Histone deacetylases (HDACs) correlates with the regulation of tumorigenesis and cell metabolism in GBM progression, and HDAC inhibitors report to have therapeutic efficacy in GBM and other neurological diseases; however, GBM prevention and therapy by HDAC inhibition lacks a mechanism in the focus of metabolic reprogramming.
METHODS
HDAC2 highly express in GBM and is analyzed in TCGA/GEPIA databases. Therefore, HDAC2 knockdown affects GBM cell death. Analysis of RNA sequencing and qRT-PCR reveals that miR-3189 increases and GLUT3 decreases by HDAC2 knockdown. GBM tumorigenesis also examines by using in vivo orthotopic xenograft tumor models. The metabolism change in HDAC2 knockdown GBM cells measures by glucose uptake, lactate production, and OCR/ECAR analysis, indicating that HDAC2 knockdown induces GBM cell death by inhibiting GLUT3.
RESULTS
Notably, GLUT3 was suppressed by increasing miR-3189, demonstrating that miR-3189-mediated GLUT3 inhibition shows an anti-tumorigenic effect and cell death by regulating glucose metabolism in HDAC2 knockdown GBM.
CONCLUSIONS
Our findings will demonstrate the central role of HDAC2 in GBM tumorigenesis through the reprogramming of glucose metabolism by controlling miR-3189-inhibited GLUT3 expression, providing a potential new therapeutic strategy for GBM treatment.
背景
表观遗传调控在胶质母细胞瘤（GBM）中频繁出现，与代谢改变高度相关。特别是，组蛋白去乙酰化酶（HDACs）与 GBM 进展中的肿瘤发生和细胞代谢调节相关，HDAC 抑制剂在 GBM 和其他神经疾病中具有治疗效果；然而，HDAC 抑制在代谢重编程的焦点缺乏 GBM 的预防和治疗机制。
方法
HDAC2 在 GBM 中高度表达，并在 TCGA/GEPIA 数据库中进行分析。因此，HDAC2 敲低会影响 GBM 细胞死亡。RNA 测序和 qRT-PCR 分析表明，HDAC2 敲低会增加 miR-3189 并减少 GLUT3。还通过体内原位异种移植肿瘤模型来检查 GBM 肿瘤发生。通过葡萄糖摄取、乳酸生成和 OCR/ECAR 分析测量 HDAC2 敲低 GBM 细胞中的代谢变化，表明 HDAC2 敲低通过抑制 GLUT3 诱导 GBM 细胞死亡。
结果
值得注意的是，GLUT3 被增加的 miR-3189 抑制，表明 miR-3189 介导的 GLUT3 抑制通过调节 HDAC2 敲低 GBM 中的葡萄糖代谢显示出抗肿瘤作用和细胞死亡。
结论
我们的研究结果将通过控制 miR-3189 抑制的 GLUT3 表达来证明 HDAC2 在 GBM 肿瘤发生中的核心作用，通过重新编程葡萄糖代谢，为 GBM 的治疗提供一种潜在的新的治疗策略。
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