Aberrant amplification of the crosstalk between canonical Wnt signaling and N-glycosylation gene DPAGT1 promotes oral cancer.
Aberrant amplification of the crosstalk between canonical Wnt signaling and N-glycosylation gene DPAGT1 promotes oral cancer.
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DOI：
10.1016/j.oraloncology.2012.01.010
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发表时间：
2012-06
期刊：
影响因子：
4.8
通讯作者：
Kukuruzinska, Maria A.
中科院分区：
文献类型：
--
作者：
Jamal, Basem;Sengupta, Pritam K.;Gao, Zhen-nan;Nita-Lazar, Mihai;Amin, Bakr;Jalisi, Sharuch;Bouchie, Meghan P.;Kukuruzinska, Maria A.
关键词：
口腔癌是最具侵袭性的上皮性恶性肿瘤之一，其发病率呈上升趋势。以往的研究表明，在口腔鳞状细胞癌(OSCC)的一组肿瘤标本中，DPAGT1基因的过度表达通过抑制E-钙粘附素的黏附功能来驱动肿瘤细胞的解聚。DPAGT1基因编码的是多利胆碱依赖的N-乙酰葡萄糖胺-1-磷酸转移酶，它是蛋白质N-糖基化代谢途径的关键调节因子。最近，我们报道了DPAGT1是典型的Wnt信号通路的靶点。在这里，我们将口腔鳞状细胞癌标本中DPAGT1的过度表达与规范的Wnt信号的异常激活联系起来。我们报告了DPAGT1启动子上β-和γ-连环蛋白的急剧增加，并将它们与Wnt抑制物Dickkopf-1(DKK-1)的表达减少相关。利用人头颈部鳞癌细胞株，我们发现DPAGT1的部分抑制减少了典型的Wnt信号，表明DPAGT1和典型的Wnt信号在正反馈环路中发挥作用。我们提供的证据表明，E-钙粘素通过耗尽核β-和γ-连环蛋白来抑制DPAGT1、规范的Wnt信号和口腔鳞癌的癌症表型，其中低糖基化的E-Cad是最有效的。这表明，在人类口腔鳞癌中，E-Cad的广泛N-糖基化削弱了其抑制典型Wnt信号和DPAGT1表达的能力。我们的研究揭示了DPAGT1/N-糖基化和典型的Wnt信号之间的一种新的相互作用，并表明这种串扰的失调是OSCC的关键机制。他们还提示，部分抑制DPAGT1可能是恢复口腔癌这些重要途径之间正常相互作用的有效途径。
Oral cancer is one of the most aggressive epithelial malignancies, whose incidence is on the rise. Previous studies have shown that in a subset of human oral squamous cell carcinoma (OSCC) tumor specimens, overexpression of the DPAGT1 gene, encoding the dolichol-P-dependent N-acetylglucoseamine-1-phosphate transferase, a key regulator of the metabolic pathway of protein N-glycosylation, drives tumor cell discohesion by inhibiting E-cadherin adhesive function. Recently, we reported that DPAGT1 was a target of the canonical Wnt signaling pathway. Here, we link overexpression of DPAGT1 in human OSCC tumor specimens to aberrant activation of canonical Wnt signaling. We report dramatic increases in β- and γ-catenins at the DPAGT1 promoter and correlate them with reduced expression of a Wnt inhibitor, Dickkopf-1 (Dkk-1). Using human squamous carcinoma cell lines of the head and neck, we show that partial inhibition of DPAGT1 reduces canonical Wnt signaling, indicating that DPAGT1 and canonical Wnt signaling function in a positive feedback loop. We provide evidence that E-cadherin inhibits DPAGT1, canonical Wnt signaling and the OSCC cancer phenotype by depleting nuclear β-and γ-catenins, with hypoglycosylated E-cadherin being the most effective.This suggests that in human OSCC, extensive N-glycosylation of E-cadherin compromises its ability to inhibit canonical Wnt signaling and DPAGT1 expression. Our studies reveal a novel interplay between DPAGT1/N-glycosylation and canonical Wnt signaling and suggest that dysregulation of this crosstalk is a key mechanism underlying OSCC. They also suggest that partial inhibition of DPAGT1 may represent an effective way to restore normal interactions among these essential pathways in oral cancer.
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影响因子：
9.8
作者：
Semb, H;Christofori, G
通讯作者：
Christofori, G
影响因子：
56.9
作者：
TAKEICHI, M
通讯作者：
TAKEICHI, M
头部和颈部鳞状细胞癌的突变景观。
DOI：
10.1126/science.1208130
发表时间：
2011-08-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Stransky N;Egloff AM;Tward AD;Kostic AD;Cibulskis K;Sivachenko A;Kryukov GV;Lawrence MS;Sougnez C;McKenna A;Shefler E;Ramos AH;Stojanov P;Carter SL;Voet D;Cortés ML;Auclair D;Berger MF;Saksena G;Guiducci C;Onofrio RC;Parkin M;Romkes M;Weissfeld JL;Seethala RR;Wang L;Rangel-Escareño C;Fernandez-Lopez JC;Hidalgo-Miranda A;Melendez-Zajgla J;Winckler W;Ardlie K;Gabriel SB;Meyerson M;Lander ES;Getz G;Golub TR;Garraway LA;Grandis JR
通讯作者：
Grandis JR
影响因子：
2.1
作者：
Komekado, Hideyuki;Yamamoto, Hideki;Kikuchi, Akira
通讯作者：
Kikuchi, Akira
影响因子：
3.7
作者：
Nita-Lazar M;Rebustini I;Walker J;Kukuruzinska MA
通讯作者：
Kukuruzinska MA