Homeobox A3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression
Homeobox A3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression
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DOI：
10.1093/neuonc/noac231
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发表时间：
2022-11-14
期刊：
影响因子：
15.9
通讯作者：
Cui，Hongjuan
中科院分区：
文献类型：
--
作者：
Yang，Rui;Zhang，Guanghui;Cui，Hongjuan
背景糖酵解代谢转录调节因子的改变与脑肿瘤的生长有关，但其潜在的分子机制仍知之甚少。方法采用敲低和过表达细胞来探讨HOXA3在细胞增殖、肿瘤形成和有氧糖酵解中的功能作用。进行染色质免疫沉淀、荧光素酶测定和蛋白质印迹来验证 HOXA3 对 HK2 和 PKM2 的调节。 PLA、免疫沉淀和 GST-pull-down 测定用于检查 HOXA3 和 KDM6A 的相互作用。结果我们报告转录因子同源框 A3 (HOXA3) 在胶质母细胞瘤 (GBM) 患者中异常高表达并预测不良预后，它转录激活有氧糖酵解，导致细胞增殖和肿瘤生长显着加速。从机械角度来看，我们发现 KDM6A（一种赖氨酸特异性去甲基酶）是 HOXA3 在调节有氧糖酵解方面的重要合作者。 HOXA3 激活 KDM6A 转录，并将 KDM6A 招募到糖酵解基因的基因组结合位点，通过消除抑制性组蛋白修饰 H3K27 三甲基化，靶向糖酵解基因进行转录激活。进一步的证据表明 HOXA3 需要 KDM6A 来转录激活有氧糖酵解和脑肿瘤生长。结论我们的研究结果提供了一种新的分子机制，将 HOXA3 介导的反式激活和 KDM6A 偶联的 H3K27 去甲基化联系起来，以调节葡萄糖代谢和 GBM 进展。
BackgroundAlterations in transcriptional regulators of glycolytic metabolism have been implicated in brain tumor growth, but the underlying molecular mechanisms remain poorly understood.MethodsKnockdown and overexpression cells were used to explore the functional roles of HOXA3 in cell proliferation, tumor formation, and aerobic glycolysis. Chromatin immunoprecipitation, luciferase assays, and western blotting were performed to verify the regulation of HK2 and PKM2 by HOXA3. PLA, Immunoprecipitation, and GST-pull-down assays were used to examine the interaction of HOXA3 and KDM6A.ResultsWe report that transcription factor homeobox A3 (HOXA3), which is aberrantly highly expressed in glioblastoma (GBM) patients and predicts poor prognosis, transcriptionally activates aerobic glycolysis, leading to a significant acceleration in cell proliferation and tumor growth. Mechanically, we identified KDM6A, a lysine-specific demethylase, as an important cooperator of HOXA3 in regulating aerobic glycolysis. HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes, targeting glycolytic genes for transcriptional activation by removing the suppressive histone modification H3K27 trimethylation. Further evidence demonstrates that HOXA3 requires KDM6A for transcriptional activation of aerobic glycolysis and brain tumor growth.ConclusionsOur findings provide a novel molecular mechanism linking HOXA3-mediated transactivation and KDM6A-coupled H3K27 demethylation in regulating glucose metabolism and GBM progression.