Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma
Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma
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Sirtuin 介导的 hnRNP A1 去乙酰化抑制肝细胞癌中的糖酵解和生长
DOI：
10.1038/s41388-019-0764-z
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发表时间：
2019-06-20
期刊：
影响因子：
8
通讯作者：
Huang, Gang
中科院分区：
文献类型：
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作者：
Yang, Hao;Zhu, Rongxuan;Huang, Gang
为了适应改变的微环境，肿瘤细胞经历了新陈代谢的转变，尽管其潜在的机制还没有完全被探索。HnRNP A1参与丙酮酸激酶(PK)mRNA的选择性剪接，使肿瘤细胞能够特异性地产生PKM2亚型。我们发现，hnRNP A1在肝癌细胞中的乙酰化状态依赖于葡萄糖的可获得性，这影响了PKM2依赖的糖酵解途径。在葡萄糖缺乏的肝癌细胞中，脱乙酰酶sirtuin家族成员SIRT1和SIRT6高表达并直接结合后使hnRNP A1脱乙酰化。我们在hnRNP A1中发现了四个赖氨酸残基，它们被SIRT1和SIRT6去乙酰化，导致肝癌细胞糖酵解的显著抑制。在正常葡萄糖条件下，去乙酰化的hnRNP A1降低了肝癌细胞中的PKM2，增加了PKM1的选择性剪接，从而降低了PK的代谢活性和非代谢的PKM2-β-连环蛋白信号通路。然而，在葡萄糖饥饿下，低水平的乙酰化hnRNP A1降低了肝癌细胞的新陈代谢，以适应营养缺乏。综上所述，sirtuin介导的hnRNP A1去乙酰化以PKM2依赖的方式抑制肝癌细胞的增殖和肿瘤的发生。这些发现表明，hnRNP A1乙酰化诱导的代谢重新编程，以适应肿瘤微环境的营养状态。
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.