Abstract：
Vestigial-like family member 3 (VGLL3) is a member of the VGLL family that serves as cofactors for TEA-domain transcription factors. Although VGLL3 is involved in the proliferation of cancer cells, the molecular mechanisms underlying VGLL3-mediated cell proliferation remain largely unknown. In this study, we found that stable expression of VGLL3 in human lung cancer A549 cells affects glutamine metabolism and increases their dependency on de novo nucleotide synthesis for proliferation. Mechanistically, VGLL3 was found to induce the expression of GART, which encodes a trifunctional enzyme that catalyzes de novo purine synthesis from glutamine. GART knockdown and the glycinamide ribonucleotide synthase, aminoimidazole ribonucleotide synthase, and glycinamide ribonucleotide formyltransferase trifunctional protein (GART) inhibitor lometrexol repressed the proliferation and survival of A549 cells stably expressing VGLL3. Mesenchymal breast cancer BT549 cells and MDA-MB-231 cells showed high expression of VGLL3, and VGLL3 knockdown was found to reduce GART expression. Lometrexol also repressed the proliferation of these breast cancer cells, whereas addition of inosine monophosphate, an important metabolite downstream of GART, rescued this repression. Taken together, these results suggest that VGLL3 induces GART expression and thereby confers de novo nucleotide-dependent cell proliferation in cancer cells.
摘要：
残余样家族成员3(VGLL3)是VGLL家族的成员,其充当TEA结构域转录因子的辅因子。尽管VGLL3参与癌细胞的增殖，VGLL3介导的细胞增殖的分子机制在很大程度上仍然未知.在这项研究中,我们发现VGLL3在人肺癌A549细胞中的稳定表达会影响谷氨酰胺代谢，并增加其对从头核苷酸合成增殖的依赖性。机械上,发现VGLL3诱导GART的表达，它编码一种催化谷氨酰胺从头合成嘌呤的三功能酶。GART敲低和甘氨酰胺核糖核苷酸合酶，氨基咪唑核糖核苷酸合酶，和甘氨酰胺核糖核苷酸甲酰基转移酶三功能蛋白（GART）抑制剂lometrexol抑制稳定表达VGLL3的A549细胞的增殖和存活。间充质乳腺癌BT549细胞和MDA-MB-231细胞显示VGLL3的高表达，发现VGLL3敲低可降低GART表达。Lometrexol还抑制了这些乳腺癌细胞的增殖，而添加一磷酸肌苷，GART下游的重要代谢物，拯救了这种镇压。一起来看,这些结果表明,VGLL3诱导GART表达,从而赋予癌细胞从头核苷酸依赖性细胞增殖.
