The serine synthesis pathway (SSP) involving metabolic enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) drives intracellular serine biosynthesis and is indispensable for cancer cells to grow in serine-limiting environments. However, how SSP is regulated is not well understood. Here, we report that activating transcription factor 3 (ATF3) is crucial for transcriptional activation of SSP upon serine deprivation. ATF3 is rapidly induced by serine deprivation via a mechanism dependent on ATF4, which in turn binds to ATF4 and increases the stability of this master regulator of SSP. ATF3 also binds to the enhancers/promoters of PHGDH, PSAT1, and PSPH and recruits p300 to promote expression of these SSP genes. As a result, loss of ATF3 expression impairs serine biosynthesis and the growth of cancer cells in the serine-deprived medium or in mice fed with a serine/glycine-free diet. Interestingly, ATF3 expression positively correlates with PHGDH expression in a subset of TCGA cancer samples.

涉及代谢酶磷酸甘油酸脱氢酶 (PHGDH)、磷酸丝氨酸氨基转移酶 1 (PSAT1) 和磷酸丝氨酸磷酸酶 (PSPH) 的丝氨酸合成途径 (SSP) 驱动细胞内丝氨酸生物合成，对于癌细胞在丝氨酸限制环境中生长是必不可少的。然而，SSP 是如何被监管的还不是很清楚。在这里，我们报告激活转录因子 3 (ATF3) 对于丝氨酸剥夺后 SSP 的转录激活至关重要。ATF3 通过依赖于 ATF4 的机制被丝氨酸剥夺迅速诱导，ATF4 反过来与 ATF4 结合并增加 SSP 主调节器的稳定性。ATF3 还与PHGDH、PSAT1和PSPH的增强子/启动子结合并募集 p300 来促进这些 SSP 基因的表达。因此，在缺乏丝氨酸的培养基或喂食无丝氨酸/甘氨酸饮食的小鼠中，ATF3表达的丧失会损害丝氨酸的生物合成和癌细胞的生长。有趣的是，ATF3表达与一部分 TCGA 癌症样本中的PHGDH表达呈正相关。