The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity.
The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity.
复制标题
DOI：
10.7554/elife.29830
复制
发表时间：
2017-11-07
期刊：
影响因子：
7.7
通讯作者：
Borden KL
中科院分区：
文献类型：
--
作者：
Zahreddine HA;Culjkovic-Kraljacic B;Emond A;Pettersson F;Midura R;Lauer M;Del Rincon S;Cali V;Assouline S;Miller WH;Hascall V;Borden KL
微环境提供了支持肿瘤生长的功能基质。透明质酸（HA）是这种结构的主要成分。虽然HA在恶性肿瘤中的作用是明确的，但在癌症中驱动其生物合成的机制知之甚少。我们发现，真核生物的翻译起始因子eIF 4 E，一种癌蛋白，驱动HA的生物合成。eIF 4 E刺激合成HA、UDP-葡糖醛酸和UDP-N-乙酰基-葡糖胺结构单元的酶以及形成二糖链的透明质酸合酶的产生。引人注目的是，单独抑制eIF 4 E抑制HA水平与用透明质酸酶直接靶向HA一样有效。不寻常的是，HA保留在高eIF 4 E细胞的表面上，而不是被挤出到细胞外空间。表面相关的HA是eIF 4 E的致癌活性所必需的，这表明eIF 4 E增强致癌HA程序。这些研究为驱动HA产生的机制提供了独特的见解，并证明癌蛋白可以协同HA生物合成以驱动恶性肿瘤。
The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood. We show that the eukaryotic translation initiation factor eIF4E, an oncoprotein, drives HA biosynthesis. eIF4E stimulates production of enzymes that synthesize the building blocks of HA, UDP-Glucuronic acid and UDP-N-Acetyl-Glucosamine, as well as hyaluronic acid synthase which forms the disaccharide chain. Strikingly, eIF4E inhibition alone repressed HA levels as effectively as directly targeting HA with hyaluronidase. Unusually, HA was retained on the surface of high-eIF4E cells, rather than being extruded into the extracellular space. Surface-associated HA was required for eIF4E’s oncogenic activities suggesting that eIF4E potentiates an oncogenic HA program. These studies provide unique insights into the mechanisms driving HA production and demonstrate that an oncoprotein can co-opt HA biosynthesis to drive malignancy.