Transcriptional Activation of Chac1 and Other Atf4-Target Genes Induced by Extracellular l-Serine Depletion is negated with Glycine Consumption in Hepa1-6 Hepatocarcinoma Cells

• Published in: Nutrients 2020-10, Vol.12 (10), p.3018
• Main Authors: Hamano, Momoko, Tomonaga, Shozo, Osaki, Yusuke, Oda, Hiroaki, Kato, Hisanori, Furuya, Shigeki
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - metabolism; Amino acids; Animals; Antibodies; Biological Availability; Cancer; Carcinoma, Hepatocellular - genetics; Cell growth; Cell Line, Tumor; Chac1; D-3-Phosphoglycerate dehydrogenase; Dehydrogenases; Depletion; Embryo fibroblasts; gamma-Glutamylcyclotransferase - metabolism; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genes; Glycine; Glycine - metabolism; Hepatoma; Hydroxymethyl and Formyl Transferases - metabolism; Intracellular; l -serine deficiency; L-Serine; Liver cancer; Liver Neoplasms - genetics; Metabolism; Mice; Phgdh; Phosphatase; Phosphoglycerate Dehydrogenase - metabolism; Potash; Protein transport; Proteins; Serine - pharmacokinetics; Shmt; Transcription activation; Transcriptional Activation - genetics; Up-Regulation - genetics
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu12103018

Mouse embryonic fibroblasts lacking D-3-phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step of de novo synthesis of l-serine, are particularly sensitive to depletion of extracellular L-serine. In these cells, depletion of l-serine leads to a rapid reduction of intracellular L-serine, cell growth arrest, and altered expression of a wide variety of genes. However, it remains unclear whether reduced availability of extracellular l-serine elicits such responses in other cell types expressing . Here, we show in the mouse hepatoma cell line Hepa1-6 that extracellular l-serine depletion transiently induced transcriptional activation of Atf4-target genes, including cation transport regulator-like protein 1 ( . Expression levels of these genes returned to normal 24 h after l-serine depletion, and were suppressed by the addition of l-serine or glycine in the medium. Extracellular l-serine depletion caused a reduction of extracellular and intracellular glycine levels but maintained intracellular l-serine levels in the cells. Further, Phgdh and serine hydroxymethyltransferase 2 (Shmt2) were upregulated after l-serine depletion. These results led us to conclude that the Atf4-mediated gene expression program is activated by extracellular l-serine depletion in Hepa1-6 cells expressing , but is antagonized by the subsequent upregulation of l-serine synthesis, mainly from autonomous glycine consumption.