Mutant GTF2I induces cell transformation and metabolic alterations in thymic epithelial cells.,Cell Death and Differentiation

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Mutant GTF2I induces cell transformation and metabolic alterations in thymic epithelial cells.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2020-02-07 , DOI: 10.1038/s41418-020-0502-7
In-Kyu Kim ₁ , Guanhua Rao ₁ , Xiaoliang Zhao ₁ , Ruzong Fan ₁ , Maria Laura Avantaggiati ₁ , Yisong Wang _{1,

2} , Yu-Wen Zhang ₁ , Giuseppe Giaccone ₁

Affiliation

The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism. Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial cells.

中文翻译：

突变 GTF2I 诱导胸腺上皮细胞的细胞转化和代谢改变。

胸腺上皮肿瘤 (TET) 的发病机制知之甚少。最近我们报道了 TET 中 GTF2I 基因错义突变的频繁发生，并假设 GTF2I 突变可能有助于胸腺肿瘤的发生。突变体 TFII-I 的表达改变了正常胸腺上皮细胞的转录组并上调了几个致癌基因。Gtf2i L424H 敲入细胞表现出细胞转化、非整倍性，并在葡萄糖剥夺或 DNA 损伤下增加肿瘤生长和存活。Gtf2i 突变还增加了几种糖酵解酶 cyclooxygenase-2 的表达，并引起脂质代谢的改变。Gtf2i 突变导致环加氧酶-2 表达升高是代谢应激和胸腺上皮细胞细胞转化所必需的。

更新日期：2020-02-07

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