SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells

J Biol Chem. 2009 Jan 30;284(5):3334-3344. doi: 10.1074/jbc.M808989200.

Mami Takahata ¹, Yasumichi Inoue ², Hitoshi Tsuda ³, Issei Imoto ⁴, Daizo Koinuma ², Makoto Hayashi ², Takashi Ichikura ⁵, Takao Yamori ⁶, Koichi Nagasaki ⁷, Mika Yoshida ⁸, Masao Matsuoka ⁸, Kazuhiro Morishita ⁹, Keiko Yuki ¹⁰, Aki Hanyu ², Keiji Miyazawa ¹⁰, Johji Inazawa ⁴, Kohei Miyazono ¹⁰, Takeshi Imamura ¹¹

Affiliations

1 Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo 135-8550; Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
2 Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
3 Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513.
4 Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510.
5 Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513.
6 Division of Molecular Pharmacology, the Cancer Chemotherapy Center of the JFCR, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
7 Genome Center of the JFCR, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
8 Laboratory of Virus Immunology, Institute of Virus Research, Kyoto University, 53 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507.
9 Department of Biochemistry, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, Miyazaki 889-1692, Japan.
10 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
11 Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo 135-8550. Electronic address: [email protected].

PMID: 19049980 DOI: 10.1074/jbc.M808989200

Abstract

Chromosomal amplification occurs frequently in solid tumors and is associated with poor prognosis. Several reports demonstrated the cooperative effects of oncogenic factors in the same amplicon during Cancer development. However, the functional correlation between the factors remains unclear. Transforming growth factor (TGF)-beta signaling plays important roles in cytostasis and normal epithelium differentiation, and alterations in TGF-beta signaling have been identified in many malignancies. Here, we demonstrated that transcriptional co-repressors of TGF-beta signaling, SKI and MDS1/EVI1-like gene 1 (MEL1), were aberrantly expressed in MKN28 gastric Cancer cells by chromosomal co-amplification of 1p36.32. SKI and MEL1 knockdown synergistically restored TGF-beta responsiveness in MKN28 cells and reduced tumor growth in vivo. MEL1 interacted with SKI and inhibited TGF-beta signaling by stabilizing the inactive Smad3-SKI complex on the promoter of TGF-beta target genes. These findings reveal a novel mechanism where distinct transcriptional co-repressors are co-amplified and functionally interact, and provide molecular targets for gastric Cancer treatment.

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