SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells.
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.
Takahata
Mami
M
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.
Inoue
Yasumichi
Y
Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
Tsuda
Hitoshi
H
Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513.
Imoto
Issei
I
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.
Koinuma
Daizo
D
Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
Hayashi
Makoto
M
Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
Ichikura
Takashi
T
Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513.
Yamori
Takao
T
Division of Molecular Pharmacology, the Cancer Chemotherapy Center of the JFCR, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
Nagasaki
Koichi
K
Genome Center of the JFCR, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
Yoshida
Mika
M
Laboratory of Virus Immunology, Institute of Virus Research, Kyoto University, 53 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507.
Matsuoka
Masao
M
Laboratory of Virus Immunology, Institute of Virus Research, Kyoto University, 53 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507.
Morishita
Kazuhiro
K
Department of Biochemistry, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, Miyazaki 889-1692, Japan.
Yuki
Keiko
K
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Hanyu
Aki
A
Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6 Ariake, Koto-ku, Tokyo 135-8550.
Miyazawa
Keiji
K
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Inazawa
Johji
J
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.
Miyazono
Kohei
K
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Imamura
Takeshi
T
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: timamura-ind@umin.ac.jp.
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; C416371:PRDM16 protein, human; D011518:Proto-Oncogene Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C060614:SKI protein, human