Lee Jong-Hyuk, Jang Hyonchol, Lee Soon-Min, Lee Ji-Eun, Choi Jinmi, Kim Tae Wan, Cho Eun-Jung, Youn Hong-Duk
Department of Biomedical Sciences, National Creative Research Center for Epigenome Reprogramming Network, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Korea; Department of Biochemistry and Molecular Biology, National Creative Research Center for Epigenome Reprogramming Network, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Korea.
FEBS J. 2015 Jan;282(2):361-71. doi: 10.1111/febs.13139. Epub 2014 Nov 23.
ATP citrate lyase (ACLY) is a key enzyme that is involved in de novo lipogenesis by catalyzing conversion of cytosolic citrate into acetyl CoA and oxaloacetate. Up-regulation of ACLY in various types of tumors enhances fatty acid synthesis and supplies excess acetyl CoA for histone acetylation. However, there is evidence that its enzymatic activity alone is insufficient to explain ACLY silencing-mediated growth arrest in tumor cells. In this study, we found that ACLY knockdown in primary human cells triggers cellular senescence and activation of tumor suppressor p53. Provision of acetyl CoA to ACLY knockdown cells did not alleviate ACLY silencing-induced p53 activation, suggesting an independent role for ACLY activity. Instead, ACLY physically interacted with the catalytic subunit of AMP-activated protein kinase (AMPK) and inhibited AMPK activity. The activation of AMPK under ACLY knockdown conditions may lead to p53 activation, ultimately leading to cellular senescence. In cancer cells, ACLY silencing-induced p53 activation facilitated DNA damage-induced cell death. Taken together, our results suggest a novel function of ACLY in cellular senescence and tumorigenesis.
ATP柠檬酸裂解酶（ACLY）是一种关键酶，通过催化胞质柠檬酸转化为乙酰辅酶A和草酰乙酸参与从头脂肪生成。在各类肿瘤中，ACLY的上调增强了脂肪酸合成，并为组蛋白乙酰化提供了过量的乙酰辅酶A。然而，有证据表明，仅其酶活性不足以解释ACLY沉默介导的肿瘤细胞生长停滞。在本研究中，我们发现原代人细胞中ACLY的敲低会触发细胞衰老和肿瘤抑制因子p53的激活。向ACLY敲低的细胞提供乙酰辅酶A并不能减轻ACLY沉默诱导的p53激活，这表明ACLY活性具有独立作用。相反，ACLY与AMP激活的蛋白激酶（AMPK）的催化亚基发生物理相互作用并抑制AMPK活性。在ACLY敲低条件下AMPK的激活可能导致p53激活，最终导致细胞衰老。在癌细胞中，ACLY沉默诱导的p53激活促进了DNA损伤诱导的细胞死亡。综上所述，我们的结果表明ACLY在细胞衰老和肿瘤发生中具有新功能。
