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The transcription factors aryl hydrocarbon receptor and MYC cooperate in the regulation of cellular metabolism.
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2020-08-28 , DOI: 10.1074/jbc.ac120.014189
M Carmen Lafita-Navarro 1 , Lizbeth Perez-Castro 1 , Lauren G Zacharias 2 , Spencer Barnes 3 , Ralph J DeBerardinis 2, 4 , Maralice Conacci-Sorrell 5, 6, 7
Affiliation  

The transcription factor AHR (aryl hydrocarbon receptor) drives the expression of genes involved in detoxification pathways in cells exposed to pollutants and other small molecules. Moreover, AHR supports transcriptional programs that promote ribosome biogenesis and protein synthesis in cells stimulated to proliferate by the oncoprotein MYC. Thus, AHR is necessary for the proliferation of MYC-overexpressing cells. To define metabolic pathways in which AHR cooperates with MYC in supporting cell growth, here we used LC–MS–based metabolomics to examine the metabolome of MYC-expressing cells upon AHR knockdown. We found that AHR knockdown reduced lactate, S-lactoylglutathione, N-acetyl-l-alanine, 2-hydroxyglutarate, and UMP levels. Using our previously obtained RNA sequencing data, we found that AHR mediates the expression of the UMP-generating enzymes dihydroorotate dehydrogenase (quinone) (DHODH) and uridine monophosphate synthetase (UMPS), as well as lactate dehydrogenase A (LDHA), establishing a mechanism by which AHR regulates lactate and UMP production in MYC-overexpressing cells. AHR knockdown in glioblastoma cells also reduced the expression of LDHA (and lactate), DHODH, and UMPS but did not affect UMP levels, likely because of compensatory mechanisms in these cells. Our results indicate that AHR contributes to the regulation of metabolic pathways necessary for the proliferation of transformed cells.

中文翻译:

转录因子芳烃受体和MYC协同调节细胞代谢。

转录因子 AHR(芳烃受体)驱动暴露于污染物和其他小分子的细胞中参与解毒途径的基因的表达。此外,AHR 支持转录程序,在被癌蛋白 MYC 刺激增殖的细胞中促进核糖体生物发生和蛋白质合成。因此,AHR 是 MYC 过表达细胞增殖所必需的。为了确定 AHR 与 MYC 合作支持细胞生长的代谢途径,在这里我们使用基于 LC-MS 的代谢组学来检查 AHR 敲低后表达 MYC 的细胞的代谢组。我们发现 AHR 敲低降低了乳酸、S-乳酰谷胱甘肽、N-乙酰基-l-丙氨酸、2-羟基戊二酸和 UMP 水平。使用我们之前获得的 RNA 测序数据,我们发现 AHR 介导了产生 UMP 的酶二氢乳清酸脱氢酶 (醌) (DHODH) 和尿苷单磷酸合成酶 (UMPS) 以及乳酸脱氢酶 A (LDHA) 的表达,从而建立了 AHR 调节乳酸和 UMP 产生的机制在过表达 MYC 的细胞中。胶质母细胞瘤细胞中的 AHR 敲低也降低了 LDHA(和乳酸)、DHODH 和 UMPS 的表达,但不影响 UMP 水平,可能是因为这些细胞中的代偿机制。我们的结果表明 AHR 有助于调节转化细胞增殖所需的代谢途径。建立 AHR 调节 MYC 过表达细胞中乳酸和 UMP 产生的机制。胶质母细胞瘤细胞中的 AHR 敲低也降低了 LDHA(和乳酸)、DHODH 和 UMPS 的表达,但不影响 UMP 水平,可能是因为这些细胞中的代偿机制。我们的结果表明,AHR 有助于调节转化细胞增殖所需的代谢途径。建立 AHR 调节 MYC 过表达细胞中乳酸和 UMP 产生的机制。胶质母细胞瘤细胞中的 AHR 敲低也降低了 LDHA(和乳酸)、DHODH 和 UMPS 的表达,但不影响 UMP 水平,可能是因为这些细胞中的代偿机制。我们的结果表明 AHR 有助于调节转化细胞增殖所需的代谢途径。
更新日期:2020-08-28
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