Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma.
Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma.
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DHODH 表达升高通过稳定食管鳞状细胞癌中的 β-catenin 促进细胞增殖
DOI：
10.1038/s41419-020-03044-1
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发表时间：
2020-10-15
影响因子：
9
通讯作者：
Cui Y
中科院分区：
文献类型：
--
作者：
Qian Y;Liang X;Kong P;Cheng Y;Cui H;Yan T;Wang J;Zhang L;Liu Y;Guo S;Cheng X;Cui Y
二氢乳清酸脱氢酶（DHODH）作为嘧啶从头合成的关键酶，在多种恶性肿瘤中表达水平升高，其促肿瘤作用被认为与其嘧啶合成功能有关。在这里，我们揭示了一个有趣的潜在机制，DHODH调节β-catenin信号在食管鳞状细胞癌（ESCC）。我们证明DHODH直接与β-catenin的NH 2末端结合，从而中断GSK 3 β与β-catenin的相互作用，并导致β-catenin降解的消除和β-catenin在细胞核中的积累，这反过来又导致β-catenin下游基因的激活，包括CCND 1，E2 F3，Nanog和OCT 4。我们进一步证明了DHODH对β-catenin的调节不依赖于DHODH的催化活性。单因素和多因素分析提示DHODH表达可能是影响食管鳞癌患者预后的独立因素。总的来说，我们的研究强调了DHODH介导的β-catenin信号传导的关键作用，并表明DHODH可能作为一个多功能的开关，从催化嘧啶代谢到调节ESCC中的肿瘤相关信号通路。
As a key enzyme in de novo pyrimidine biosynthesis, the expression level of dihydroorotate dehydrogenase (DHODH) has been reported to be elevated in various types of malignant tumors and its tumor-promoting effect was considered to relate to its pyrimidine synthesis function. Here, we revealed one intriguing potential mechanism that DHODH modulated β-catenin signaling in esophageal squamous cell carcinoma (ESCC). We demonstrated that DHODH directly bound to the NH2 terminal of β-catenin, thereby, interrupting the interaction of GSK3β with β-catenin and leading to the abrogation of β-catenin degradation and accumulation of β-catenin in the nucleus, which in turn, resulted in the activation of β-catenin downstream genes, includingCCND1,E2F3,Nanog, andOCT4. We further demonstrated that the regulation of β-catenin by DHODH was independent of DHODH catalyzing activity. Univariate and multivariate analyses suggested that DHODH expression might be an independent prognostic factor for ESCC patients. Collectively, our study highlights the pivotal role of DHODH mediated β-catenin signaling and indicates that DHODH may act as a multi-functional switcher from catalyzing pyrimidine metabolism to regulating tumor-related signaling pathways in ESCC.
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影响因子：
16.6
作者：
Ladds MJGW;van Leeuwen IMM;Drummond CJ;Chu S;Healy AR;Popova G;Pastor Fernández A;Mollick T;Darekar S;Sedimbi SK;Nekulova M;Sachweh MCC;Campbell J;Higgins M;Tuck C;Popa M;Safont MM;Gelebart P;Fandalyuk Z;Thompson AM;Svensson R;Gustavsson AL;Johansson L;Färnegårdh K;Yngve U;Saleh A;Haraldsson M;D'Hollander ACA;Franco M;Zhao Y;Håkansson M;Walse B;Larsson K;Peat EM;Pelechano V;Lunec J;Vojtesek B;Carmena M;Earnshaw WC;McCarthy AR;Westwood NJ;Arsenian-Henriksson M;Lane DP;Bhatia R;McCormack E;Laín S
通讯作者：
Laín S
影响因子：
15.9
作者：
Li, Ming-Yang;Fan, Lin-Ni;Wang, Zhe
通讯作者：
Wang, Zhe
影响因子：
11.4
作者：
Christian, Sven;Merz, Claudia;Janzer, Andreas
通讯作者：
Janzer, Andreas
DOI：
10.1016/s0969-2126(00)00077-0
发表时间：
2000-01-15
期刊：
STRUCTURE WITH FOLDING & DESIGN
影响因子：
--
作者：
Liu, SP;Neidhardt, EA;Clardy, J
通讯作者：
Clardy, J
影响因子：
15.9
作者：
Echizenya, Smile;Ishii, Yukiko;Kondo, Toru
通讯作者：
Kondo, Toru