A novel lncRNA MDHDH suppresses glioblastoma multiforme by acting as a scaffold for MDH2 and PSMA1 to regulate NAD+ metabolism and autophagy.
A novel lncRNA MDHDH suppresses glioblastoma multiforme by acting as a scaffold for MDH2 and PSMA1 to regulate NAD+ metabolism and autophagy.
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一种新型 lncRNA MDHDH 通过充当 MDH2 和 PSMA1 的支架来调节 NAD 代谢和自噬，从而抑制多形性胶质母细胞瘤
DOI：
10.1186/s13046-022-02543-7
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发表时间：
2022-12-17
影响因子：
11.3
通讯作者：
Liu, Qian
中科院分区：
文献类型：
--
作者：
He, Dong;Xin, Tao;Pang, Bo;Sun, Jun;Liu, Zi Hao;Qin, Zhen;Ji, Xiao Shuai;Yang, Fan;Wei, Yan Bang;Wang, Zi Xiao;Gao, Jia Jia;Pang, Qi;Liu, Qian
为了鉴定胶质瘤中与烟酰胺腺嘌呤二核苷酸（NAD+）代谢相关的潜在靶点，我们使用RNA免疫沉淀法鉴定了一种新的长链非编码RNA，命名为苹果酸脱氢酶降解辅助蛋白（MDDH）（NONCODE注释ID：NONHSAT 138800.2，NCBI参考序列：NR_028345），其与MDH 2（苹果酸脱氢酶2）结合，MDH 2在多形性胶质母细胞瘤（GBM）中下调并与代谢调节相关。然而，其在GBM进展中的潜在机制尚未得到很好的研究。为了探讨MDDH的临床意义，我们分析了其在公开数据集中的表达水平，并收集了山东大学附属山东省立医院的临床样本。使用包括FISH/CISH、CCK 8、EdU、伤口愈合和transwell测定的功能测定来确定MDDH的细胞/亚细胞定位、组织表达谱和抗癌作用。此外，RNA pulldown，质谱RNA免疫沉淀，免疫共沉淀，JC-1探针，和细胞能量产生测定用于确定MDDH在GBM的发展机制。进行动物实验以确定MDHDH在体内GBM中的抗肿瘤作用。在公开的数据集中，与GTEx正常脑组织相比，GBM和LGG中MDHDH表达显著下调。组织芯片结果显示MDHDH表达水平与肿瘤分级呈负相关。MDDH表达的改变导致GBM细胞在体外和体内的增殖、迁移和侵袭的显著变化。从机制上讲，我们发现MDDH直接与MDH 2和PSMA 1（20 S蛋白酶体核心亚基α 1型）结合作为分子支架，并通过促进泛素化MDH 2与蛋白酶体的结合来加速MDH 2的降解。MDH 2的降解随后导致线粒体膜电位和NAD+/NADH比率的变化，这阻碍了胶质瘤细胞中的糖酵解。总之，本研究拓宽了我们对lncRNA在GBM中功能的理解。我们证明了肿瘤抑制因子MDHDH可能作为一种临床生物标志物，并且MDHDH的过表达可能是一种新的协同策略，用于增强基于代谢、基于表观遗传和基于自噬调节的治疗，对多形性胶质母细胞瘤患者具有临床益处。在线版本包含补充材料，可通过10.1186/s13046-022-02543-7获得。
To identify potential targets related to nicotinamide adenine dinucleotide (NAD+) metabolism in gliomas, we used RNA immunoprecipitation to identify a novel long noncoding RNA renamed malate dehydrogenase degradation helper (MDHDH) (NONCODE annotation ID: NONHSAT138800.2, NCBI Reference Sequence: NR_028345), which bound to MDH2 (malate dehydrogenase 2), that is downregulated in glioblastoma multiforme (GBM) and associated with metabolic regulation. However, its underlying mechanisms in the progression of GBM have not been well studied. To investigate the clinical significance of MDHDH, we analyzed its expression levels in publicly available datasets and collected clinical samples from Shandong Provincial Hospital, affiliated with Shandong University. Functional assays, including FISH/CISH, CCK8, EdU, wound healing, and transwell assays, were used to determine the cellular/subcellular localization, tissue expression profile and anti-oncogenic role of MDHDH. Furthermore, RNA pulldown, mass spectrometry RNA immunoprecipitation, coimmunoprecipitation, JC-1 probe, and cell energy-production assays were used to determine the mechanisms of MDHDH in the development of GBM. Animal experiments were conducted to determine the antitumorigenic role of MDHDH in GBM in vivo. In public datasets, MDHDH expression was significantly downregulated in GBM and LGG compared with GTEx normal brain tissues. The results of the tissue microarray showed that the MDHDH expression level negatively correlated with the tumor grade. Altered MDHDH expression led to significant changes in the proliferation, migration and invasion of GBM cells both in vitro and in vivo. Mechanistically, we found that MDHDH directly bound to MDH2 and PSMA1 (20S proteasomal core subunit alpha-type 1) as a molecular scaffold and accelerated the degradation of MDH2 by promoting the binding of ubiquitinated MDH2 to the proteasome. The degradation of MDH2 subsequently led to changes in the mitochondrial membrane potential and NAD+/NADH ratio, which impeded glycolysis in glioma cells. In conclusion, this study broadened our understanding of the functions of lncRNAs in GBM. We demonstrated that the tumor suppressor MDHDH might act as a clinical biomarker and that the overexpression of MDHDH might be a novel synergistic strategy for enhancing metabolism-based, epigenetic-based, and autophagy regulation-based therapies with clinical benefits for glioblastoma multiforme patients. The online version contains supplementary material available at 10.1186/s13046-022-02543-7.
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影响因子：
14.9
作者：
Li Y;Li L;Wang Z;Pan T;Sahni N;Jin X;Wang G;Li J;Zheng X;Zhang Y;Xu J;Yi S;Li X
通讯作者：
Li X
DOI：
10.1038/nrc.2017.99
发表时间：
2018-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
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通讯作者：
Slack FJ
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1093/bioinformatics/btt495
发表时间：
2013-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Agostini F;Zanzoni A;Klus P;Marchese D;Cirillo D;Tartaglia GG
通讯作者：
Tartaglia GG