VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression
VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression
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DOI：
10.1002/jcb.30251
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发表时间：
2022-04-17
影响因子：
4
通讯作者：
Yamaguchi, Noritaka
中科院分区：
文献类型：
--
作者：
Kawamura, Tomohiro;Takehora, Yuki;Yamaguchi, Noritaka
退化样家族成员 3 (VGLL3) 是 VGLL 家族的成员，充当 TEA 域转录因子的辅助因子。尽管 VGLL3 参与癌细胞的增殖，但 VGLL3 介导的细胞增殖的分子机制仍然很大程度上未知。在这项研究中，我们发现人肺癌A549细胞中VGLL3的稳定表达会影响谷氨酰胺代谢并增加其增殖对从头核苷酸合成的依赖性。从机制上讲，VGLL3 可诱导 GART 的表达，GART 编码一种三功能酶，可催化谷氨酰胺从头合成嘌呤。 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) 抑制剂洛美曲索抑制稳定表达 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高表达，并且发现VGLL3敲低可减少GART表达。洛美曲索还抑制了这些乳腺癌细胞的增殖，而添加肌苷单磷酸（GART 下游的一种重要代谢物）则挽救了这种抑制作用。综上所述，这些结果表明 VGLL3 诱导 GART 表达，从而在癌细胞中赋予从头核苷酸依赖性细胞增殖作用。
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.