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Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter

Oncogene volume 26, pages 4499–4512 (2007)Cite this article

Abstract

The gene for tyrosine-kinase receptor Ron (MST1R) resides in the chromosome 3p21.3 region, frequently affected in common human malignancies. The gene generates two transcripts, 5 and 2 kb-long, full-length Ron (flRon) and short-form Ron (sfRon), respectively. Here, we show for the first time that the variegated Ron expression is associated with variations in the methylation patterns of two distinct CpG islands in Ron proximal promoter. Widespread hypermethylation associates with lack of flRon whereas hypermethylation of the distal island associates with transcription of sfRon, a constitutively active tyrosine-kinase that drives cell proliferation. sfRon inhibition with kinase-dead transgenes decreases cancer cell growth and induces cellular differentiation. sfRon could be a new drug target in cancer types in which it contributes to tumor progression.

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Acknowledgements

The authors thank Massimiliano Andreazzoli and Alexei Miagkov (critical comments on the manuscript), Laura Geil (editing), Vera Matrosova (immunofluorescence), Marco Onorati and Andrea Ripoli (statistical analysis). ERZ was supported by the Swedish Cancer Society, the Swedish Research Council, STINT, the Swedish Institute, the Royal Swedish Academy of Sciences, Karolinska Institute and INTAS. TI and EB were partially supported by Russian Foundation of Basic Research, Grant Number: 04-04-49074 and 04-04-48112. MIL was funded by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. The content of the publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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Authors and Affiliations

  1. Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    D Angeloni, A Danilkovitch-Miagkova & M I Lerman

  2. MTC, Karolinska Institute, Stockholm, Sweden

    T Ivanova & E Zabarovsky

  3. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Institute of Carcinogenesis, Moscow, Russia

    T Ivanova

  4. Scuola Superiore Sant'Anna and Institute of Clinical Physiology – CNR, Pisa, Italy

    D Angeloni

  5. The Laboratory of Molecular Diagnostics, Russian State Genetics Center, Moscow, Russia

    E Braga

  6. Now at Osiris Therapeutics Inc., 2001 Aliceanna Street, Baltimore, MD, USA

    A Danilkovitch-Miagkova

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  1. D Angeloni
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Correspondence to D Angeloni.

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Angeloni, D., Danilkovitch-Miagkova, A., Ivanova, T. et al. Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter. Oncogene 26, 4499–4512 (2007). https://doi.org/10.1038/sj.onc.1210238

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