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SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity

Nature Genetics volume 28, pages 29–35 (2001)Cite this article

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer death, but the molecular mechanism for its development beyond its initiation has not been well characterized. Suppressor of cytokine signaling (SOCS-1; also known as JAB and SSI-1) switches cytokine signaling 'off' by means of its direct interaction with Janus kinase (JAK). We identified aberrant methylation in the CpG island of SOCS-1 that correlated with its transcription silencing in HCC cell lines. The incidence of aberrant methylation was 65% in the 26 human primary HCC tumor samples analyzed. Moreover, the restoration of SOCS-1 suppressed both growth rate and anchorage-independent growth of cells in which SOCS-1 was methylation-silenced and JAK2 was constitutively activated. This growth suppression was caused by apoptosis and was reproduced by AG490, a specific, chemical JAK2 inhibitor that reversed constitutive phosphorylation of STAT3 in SOCS-1 inactivated cells. The high prevalence of the aberrant SOCS-1 methylation and its growth suppression activity demonstrated the importance of the constitutive activation of the JAK/STAT pathway in the development of HCC. Our results also indicate therapeutic strategies for the treatment of HCC including use of SOCS-1 in gene therapy and inhibition of JAK2 by small molecules, such as AG490.

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Figure 1: Correlation of DNA methylation and loss of expression of SOCS-1 in HCC cell lines.
Figure 2: Alteration of the matrix association at the SOCS-1 locus.
Figure 3: MSP analysis of 26 primary HCC samples in the SOCS-1 CpG island.
Figure 4: Constitutive activation of the JAK/STAT pathway in SOCS-1 methylation-silenced HCC cell lines.
Figure 5: Effects of JAK2 inhibition by restoration of SOCS-1 or AG490.

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Acknowledgements

We thank A. Hancock and E. Spillare for technical assistance; M. Rountree for technical advice; S. Baylin for critical comments on the manuscript; and S. Tamai for providing liver samples. H. Yoshikawa was supported in part by the NCI-JFCR scientist exchange program. Supported in part by P50 CA58184.

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Authors and Affiliations

  1. The Johns Hopkins University School of Medicine, The Oncology Center, Baltimore, Maryland, USA

    Hirohide Yoshikawa, Jasper E. Manning & James G. Herman

  2. Nara Institute of Science and Technology, Ikoma, Nara, Japan

    Kenichi Matsubara

  3. Shanghai Cancer Institute, Shanghai, PRC

    Geng-Sun Qian

  4. The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA

    Peta Jackson & John D. Groopman

  5. Laboratory of Human Carcinogenesis, NCI, NIH, Bethesda, Maryland, USA

    Curtis C. Harris

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  1. Hirohide Yoshikawa
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Correspondence to James G. Herman.

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Yoshikawa, H., Matsubara, K., Qian, GS. et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 28, 29–35 (2001). https://doi.org/10.1038/ng0501-29

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