Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet, cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall shed insight into cancer progression and benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. It remains unclear whether and how TFE3 responds to glucose starvation. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3–SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.

中文翻译：

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TFE3-SLC36A1轴促进肾癌细胞对葡萄糖饥饿的抵抗


对包括葡萄糖在内的营养素的更高需求是癌症的特征。人们一直在寻求“饥饿癌症”来遏制肿瘤进展。一个有趣的方案是抑制癌细胞中的葡萄糖转运蛋白 GLUT1。此外，在癌症进展过程中，癌细胞可能会遭受葡萄糖供应不足的困扰。然而，癌细胞可以以某种方式耐受葡萄糖饥饿。揭示潜在机制将有助于深入了解癌症进展并有益于癌症治疗。 TFE3 是一种已知可激活自噬基因的转录因子。 TFE3 的生理活性受营养状态响应的磷酸化触发的易位调节。我们最近报道，即使在营养充足的条件下，TFE3 也持续定位于细胞核并促进肾癌细胞增殖。目前尚不清楚 TFE3 是否以及如何对葡萄糖饥饿做出反应。在这项研究中，我们证明 TFE3 通过将细胞暴露于生理相关的葡萄糖浓度来促进肾癌细胞对葡萄糖饥饿的抵抗。我们发现葡萄糖饥饿通过增加其 O-GlcNAcylation 来触发 TFE3 蛋白稳定。此外，通过公正的功能基因组研究，我们确定了溶酶体氨基酸转运蛋白SLC36A1作为对TFE3蛋白水平敏感的TFE3靶基因。我们发现 SLC36A1 在肾癌中过度表达，从而促进 mTOR 活性和肾癌细胞增殖。重要的是，SLC36A1 水平是由葡萄糖饥饿通过 TFE3 诱导的，从而增强了细胞对葡萄糖饥饿的抵抗力。抑制 TFE3 或 SLC36A1 显着增加肾癌细胞对 GLUT1 抑制剂的敏感性。 总的来说，我们发现了一个功能性 TFE3-SLC36A1 轴，它可以响应葡萄糖饥饿并增强肾癌的饥饿耐受性。