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Sirtuin-mediated deacetylation of hnRNP A1 suppresses glycolysis and growth in hepatocellular carcinoma

Oncogene (2019) | Download Citation

Abstract

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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Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China (Nos. 81530053, 81830052, 81771858, 81602415, 81670573, 81572719, 81874202, and 81803581) and Shanghai Municipal Education Commission (Class II Plateau Disciplinary Construction Program for Medical Technology of SUMHS, 2018–2020).

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Author notes

  1. These authors contributed equally: Hao Yang, Rongxuan Zhu

Affiliations

  1. Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China

    • Hao Yang
    • , Zhaoli Zhou
    • , Beibei Liang
    • , Wenjing Ma
    •  & Gang Huang
  2. Department of Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    • Hao Yang
    • , Xiaoping Zhao
    • , Li Zhao
    • , Jianjun Liu
    •  & Gang Huang
  3. Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    • Rongxuan Zhu
  4. Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    • Liu Liu
  5. International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, China

    • Jian Zhao

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The authors declare that they have no conflict of interest.

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Correspondence to Jianjun Liu or Gang Huang.

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https://doi.org/10.1038/s41388-019-0764-z