生物
巴基斯坦卢比
乙酰化
锡尔图因
糖酵解
SIRT6型
癌症研究
肿瘤微环境
西妥因1
细胞生物学
生物化学
癌变
丙酮酸激酶
下调和上调
新陈代谢
基因
肿瘤细胞
作者
Hao Yang,Rongxuan Zhu,Xiaoping Zhao,Liu Liu,Zhaoli Zhou,Li Zhao,Beibei Liang,Wenjing Ma,Jian Zhao,Jianjun Liu,Gang Huang
出处
期刊:Oncogene
[Springer Nature]
日期:2019-03-11
卷期号:38 (25): 4915-4931
被引量:62
标识
DOI:10.1038/s41388-019-0764-z
摘要
Tumor cells undergo a metabolic shift in order to adapt to the altered microenvironment, although the underlying mechanisms have not been fully explored. HnRNP A1 is involved in the alternative splicing of the pyruvate kinase (PK) mRNA, allowing tumor cells to specifically produce the PKM2 isoform. We found that the acetylation status of hnRNP A1 in hepatocellular carcinoma (HCC) cells was dependent on glucose availability, which affected the PKM2-dependent glycolytic pathway. In the glucose-starved HCC cells, SIRT1 and SIRT6, members of deacetylase sirtuin family, were highly expressed and deacetylated hnRNP A1 after direct binding. We identified four lysine residues in hnRNP A1 that were deacetylated by SIRT1 and SIRT6, resulting in significant inhibition of glycolysis in HCC cells. Deacetylated hnRNP A1 reduced PKM2 and increased PKM1 alternative splicing in HCC cells under normal glucose conditions, thereby reducing the metabolic activity of PK and the non-metabolic PKM2-β-catenin signaling pathway. However, under glucose starvation, the low levels of acetylated hnRNP A1 reduced HCC cell metabolism to adapt to the nutrient deficiency. Taken together, sirtuin-mediated hnRNP A1 deacetylation inhibits HCC cell proliferation and tumorigenesis in a PKM2-dependent manner. These findings point to the metabolic reprogramming induced by hnRNP A1 acetylation in order to adapt to the nutritional status of the tumor microenvironment.
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