Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 5, Pages 3334-3344Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M808989200
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Vehicle Racing Commemorative Foundation, Naito Foundation,
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [21390098] Funding Source: KAKEN
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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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