Journal
ONCOTARGET
Volume 8, Issue 48, Pages 83962-83974Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20861
Keywords
IDH1; TGFBR; TGF-beta signalling; Cav1; alpha-ketoglutarate
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Funding
- National Program on Key Basic Research Project (973 Program) [2012CB910102, 2012CB967000]
- Shanghai Committee of Science and Technology [11DZ2260200]
- National Science Foundation of China [81372194, 81572300]
- Pudong Health and Family Planning Commission of Shanghai [PWZz2013-05]
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TGF-beta signalling plays an important role in fibroblasts activation and tumour progression. Here, we report that the TGFBR-IDH1-Cav1 axis promotes TGF-beta signalling in fibroblasts. Our data demonstrated that IDH1 was downregulated by TGF-beta signalling in fibroblasts, and downregulation of IDH1 increased cellular concentration of alpha-ketoglutarate (alpha-KG) by accelerating glutamine metabolization. Interestingly, alpha-KG suppressed Cav1 expression through reducing the trimethylation of histone H3K4. Furthermore, Cav1 downregulation inhibited TGFBR protein degradation. In turn, the activated TGFBR promoted TGF-beta signalling. These findings demonstrated that metabolic enzyme IDH1 regulates TGF-beta signalling by feedback mechanism through alpha-KG and TGFBR-IDH1-Cav1 axis is important for TGF-beta signalling.
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