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Epigenetic disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple lymphomas and carcinomas through hypermethylation of a common bidirectional promoter

Leukemia volume 20, pages 1173–1175 (2006)Cite this article

The Jun N-terminal kinase (JNK) subgroup of the mitogen-activated protein kinase (MAPK) superfamily is implicated in multiple signaling pathways of critical physiological processes, including apoptosis, differentiation and proliferation.1 Stress-induced JNK activation leads to cell death through activation of the mitochondrial apoptotic pathway in many cell types and also to the interferon-alpha-induced apoptosis in B-cell lymphoma.2 Some JNK member such as JNK1 can also promote the survival of BCR/ABL-transformed leukemia cells3 and is required for the survival and proliferation of B-lymphoma cells.4

We further found that, in a total of 82 tumor cell lines, the expression of these two genes was frequently downregulated or silenced in non-Hodgkin's lymphoma (94%, 15 of 16), Hodgkin's lymphoma (50%, three of six), breast (30%, three of 10), gastric (60%, six of 10) and heptacellular (67%, eight of 12) carcinoma cell lines (Figure 1c), whereas no downregulation was detected in other carcinoma cell lines examined (Figure 1e). In contrast, in all human normal tissues (including lymph node and peripheral blood mononuclear cell samples), both MAPK10 and PTPN13 were ubiquitously expressed, although at different levels (Figure 1c and d). Tumor suppressor genes can be inactivated through genetic or epigenetic mechanism, or a combination of both mechanisms. As no homozygous deletion of both genes was found in all the cell lines examined, we speculated that their silencing might be mediated through epigenetic mechanism. We analyzed the methylation status of their bidirectional promoter by methylation-specific PCR (Table 1)8. Methylation was detected invirtually all the cell lines with reduced or silenced expression, and in some cell lines, methylation completely silenced the expression of both genes (Figure 1c), which was further confirmed by high-resolution bisulfite genomic sequencing analysis7 (Figure 1f). Treatment with the demethylating agent 5-aza-2′-deoxycitidine (Aza) induced robust expression of both MAPK10 and PTPN13 in methylated cell lines (Figure 1g), indicating that methylation directly mediates their silencing. We also observed that in rare cell lines without MAPK10 expression, no methylation was detected, indicating that other mechanisms such as transcriptional repressors might also be infrequently involved.

Table 1 PCR primer sequences and reaction conditions
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Acknowledgements

We thank Dr Tzer Jing Seng for helping the array-CGH, Dr Riccardo Dalla-Favera for DLBCL cell lines and Dr Roger J Davis for the full-length MAPK10 cDNA clone. This study was supported by a Michael Kadoorie Cancer Genetics Research Fund grant.

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  1. Department of Clinical Oncology, Cancer Center, Chinese University of Hong Kong, Hong Kong

    J Ying, H Li, Y Cui, A H Y Wong & Q Tao

  2. Wellcome Trust Sanger Institute, Cambridge, UK

    C Langford

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Ying, J., Li, H., Cui, Y. et al. Epigenetic disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple lymphomas and carcinomas through hypermethylation of a common bidirectional promoter. Leukemia 20, 1173–1175 (2006). https://doi.org/10.1038/sj.leu.2404193

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