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Deregulated 14-3-3ζ and methionine adenosyltransferase α1 interplay promotes liver cancer tumorigenesis in mice and humans

Oncogene volume 40, pages 5866–5879 (2021)Cite this article

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Abstract

Methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor downregulated in hepatocellular carcinoma and cholangiocarcinoma, two of the fastest rising cancers worldwide. We compared MATα1 (protein encoded by MAT1A) interactome in normal versus cancerous livers by mass spectrometry to reveal interactions with 14-3-3ζ. The MATα1/14-3-3ζ complex was critical for the expression of 14-3-3ζ. Similarly, the knockdown and small molecule inhibitor for 14-3-3ζ (BV02), and ChIP analysis demonstrated the role of 14-3-3ζ in suppressing MAT1A expression. Interaction between MATα1 and 14-3-3ζ occurs directly and is enhanced by AKT2 phosphorylation of MATα1. Blocking their interaction enabled nuclear MATα1 translocation and inhibited tumorigenesis. In contrast, overexpressing 14-3-3ζ lowered nuclear MATα1 levels and promoted tumor progression. However, tumor-promoting effects of 14-3-3ζ were eliminated when liver cancer cells expressed mutant MATα1 unable to interact with 14-3-3ζ. Taken together, the reciprocal negative regulation that MATα1 and 14-3-3ζ exert is a key mechanism in liver tumorigenesis.

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Fig. 1: Interaction between MATα1 and 14-3-3ζ and correlation between YWHAZ and MAT1A mRNA levels in HCC grades and vascular invasion.
Fig. 2: Interaction between 14-3-3ζ and MATα1 requires MATα1 phosphorylation and lowers MATα1 nuclear content.
Fig. 3: 14-3-3ζ and AKT2 expression in liver cancers, the effects of AKT2 on MATα1 phosphorylation and interaction with 14-3-3ζ.
Fig. 4: Reciprocal regulation between YWHAZ and MAT1A.
Fig. 5: Effects of YWHAZ and BV02 on the MAT1A promoter.
Fig. 6: Effects of MAT1A, c-MYC and MAFG on the YWHAZ promoter.
Fig. 7: Effects of BV02 on the interaction between MATα1 and 14-3-3ζ, and on growth, migration, and invasion of OKER, SAMe-D, and MATα1-D cells.
Fig. 8: YWHAZ enhances cell migration, invasion, and tumor growth in part by keeping MATα1 out of the nucleus.

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  • 19 August 2021

    The name of Lucia Barbier- Torres was given incorrect in HTML version of the article. Correct is: Given name: Lucia Family name: Barbier-Torres

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Acknowledgements

This work was supported by NIH grants DK123763 (HP Yang, JM Mato and SC Lu), P01CA233452 (HP Yang, E Seki, ML Tomasi, N Bhowmick, and SC Lu), Natural Science Foundation General Program of Hunan Province NO.2018JJ2664 (T Liu), and Plan Nacional of I+D SAF2017-88041-R (JM Mato). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. These authors contributed equally: Liqing Lu, Jing Zhang, Wei Fan.

Authors and Affiliations

  1. Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Liqing Lu, Jing Zhang, Wei Fan, Yuan Li, Jiaohong Wang, Tony W. H. Li, Lucia Barbier-Torres, Ekihiro Seki, Michitaka Matsuda, Maria Lauda Tomasi, Heping Yang & Shelly C. Lu

  2. Key Laboratory of Cancer proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Liqing Lu & Ting Liu

  3. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jing Zhang

  4. Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Yuan Li & Ting Liu

  5. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Derio, Bizkaia, Spain

    José M. Mato

  6. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Neil A. Bhowmick

  7. Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Neil A. Bhowmick

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Contributions

LL and JZ, data collection, analysis and interpretation, figure preparation and drafting of the manuscript; WF and YL, data collection, analysis, interpretation and figure preparation; JW, TWHL and LBT, cell culture, analysis and interpretation; JMM, ES, and NAB, critical reading, editing of manuscript and intellectual content. TL, provided human biospecimens; MM and MLT, technical assistance; HY, data collection, analysis, interpretation, figure preparation and drafting of the manuscript. SCL, study concept and design, data interpretation, edited the manuscript, obtained funding and provided overall study supervision.

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Correspondence to Heping Yang or Shelly C. Lu.

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Lu, L., Zhang, J., Fan, W. et al. Deregulated 14-3-3ζ and methionine adenosyltransferase α1 interplay promotes liver cancer tumorigenesis in mice and humans. Oncogene 40, 5866–5879 (2021). https://doi.org/10.1038/s41388-021-01980-6

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