HOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma development.
HOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma development.
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OXA9 通过与 CRIP2 相互作用抑制 HIF-1α 介导的糖酵解，从而抑制皮肤鳞状细胞癌的发展。
DOI：
10.1038/s41467-018-03914-5
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发表时间：
2018-04-16
影响因子：
16.6
通讯作者：
Ding Z
中科院分区：
文献类型：
--
作者：
Zhou L;Wang Y;Zhou M;Zhang Y;Wang P;Li X;Yang J;Wang H;Ding Z
糖酵解重编程是许多癌症的典型特征;然而，对葡萄糖代谢重组的关键调节因子知之甚少，特别是在皮肤鳞状细胞癌（cSCC）中。在此，同源框A9（HOXA 9），癌-miR-365的直接靶点，被鉴定为在cSCC肿瘤和细胞系中显著下调。HOXA 9作为肿瘤抑制因子，通过负调控HIF-1α及其下游糖酵解调节因子HK 2、GLUT 1和PDK 1，在体外和体内抑制cSCC中的糖酵解。机制研究表明，HOXA 9-CRIP 2在糖酵解基因启动子的相互作用阻碍了HIF-1α的结合，抑制了基因的反式表达。我们的研究结果揭示了miR-365-HOXA 9-HIF-1α调节轴，有助于增强cSCC发展中的糖酵解，并可能代表cSCC治疗的干预靶点。缺氧诱导转录因子HIF-1α促进糖酵解，使细胞在应激下存活。在这里，作者使用细胞系和动物模型表明，在皮肤鳞状细胞癌中，HOXA 9作为肿瘤抑制因子，通过与CRIP 2结合抑制HIF-1α与靶基因的结合来抑制糖酵解。
Glycolytic reprogramming is a typical feature of many cancers; however, key regulators of glucose metabolism reengineering are poorly understood, especially in cutaneous squamous cell carcinoma (cSCC). Here, Homeobox A9 (HOXA9), a direct target of onco-miR-365, is identified to be significantly downregulated in cSCC tumors and cell lines. HOXA9 acts as a tumor suppressor and inhibits glycolysis in cSCC in vitro and in vivo by negatively regulating HIF-1α and its downstream glycolytic regulators, HK2, GLUT1 and PDK1. Mechanistic studies show that HOXA9-CRIP2 interaction at glycolytic gene promoters impeds HIF-1α binding, repressing gene expression in trans. Our results reveal a miR-365-HOXA9-HIF-1α regulatory axis that contributes to the enhanced glycolysis in cSCC development and may represent an intervention target for cSCC therapy. Hypoxia-inducible transcription factor HIF-1α promotes glycolysis allowing cell survival under stress. Here the authors show, using both cell lines and animal models, that in cutaneous squamous cell carcinoma HOXA9 acts as a tumor suppressor and inhibits glycolysis by associating with CRIP2 to repress HIF-1α binding to target genes.
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影响因子：
64.8
作者：
Dimmeler, S;Fleming, I;Zeiher, AM
通讯作者：
Zeiher, AM
影响因子：
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作者：
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