Abstract
Solute carrier family 35 member B4 (SLC35B4), a nucleotide sugar transporter, is capable of transporting UDP-xylose and UDP-GlcNAc from the cytoplasm to the lumen of the endoplasmic reticulum and Golgi. SLC35B4 has a pivotal role in glycosylation of biological macromolecules. However, its functional roles and regulatory mechanisms in malignant diseases remain unknown. Here, using the cDNA arrays, promoter reporter assays, and chromatin immunoprecipitation assays, we demonstrated that SLC35B4 is directly transactivated by YAP1–TEADs complex in gastric cancer (GC) cells. CCK-8, plate colony formation and soft agar assays revealed that SLC35B4 is essential for survival and proliferation in GC cells and nude mice models. SLC35B4 expression is markedly higher in GC tissues compared with control noncancerous tissues. Immunohistochemistry revealed that SLC35B4 expression is positively correlated with YAP1 expression in human GC tissues, and this correlation is also confirmed in the GC TCGA data set. GC patients with high levels of SLC35B4 expression have poorer prognosis than those with low levels of SLC35B4 expression. Collectively, our findings defined SLC35B4 as an important downstream oncogenic target of YAP1, suggesting that dysregulated signaling of a novel YAP1/SLC35B4 axis promotes GC development and progression, and this axis could be a potential candidate for prognosis and therapeutics in GC.
Highlights
Gastric cancer (GC) is a leading cause of global cancer mortality, especially in the Eastern Asian countries[1]
We provided the first evidence that Solute carrier family 35 member B4 (SLC35B4), which is transactivated by YAP1–TEADs complex, promotes GC cells survival and proliferation, and is closely associated with poor prognosis of GC patients
These results demonstrated that YAP1 could function as a driver to promote survival and proliferation in GC cells by upregulating Akt and Erk1/2 kinases activation, further confirming the important role of YAP1 in GC cells
Summary
Gastric cancer (GC) is a leading cause of global cancer mortality, especially in the Eastern Asian countries[1]. The current therapeutics, including surgical resection and chemotherapy, have improved the overall prognosis of clinical patients with GC, a high rate of recurrence and a substantially low survival rate in advanced cancer have not been solved definitely[2]. Molecular and genetic alterations in GC have provided critical. GC, to offer more clues for novel therapeutics and to identify better biomarkers for prognosis. The Hippo-YAP signaling pathway has been demonstrated to have a critical role that controls tissue homeostasis and organ size[7]. YAP1 (Yes-associated protein 1) is a major downstream effector of the Hippo pathway[8].
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