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TGFBR-IDH1-Cav1 axis promotes TGF-? signalling in cancer-associated fibroblast.

ABSTRACT: TGF-? signalling plays an important role in fibroblasts activation and tumour progression. Here, we report that the TGFBR-IDH1-Cav1 axis promotes TGF- ? signalling in fibroblasts. Our data demonstrated that IDH1 was downregulated by TGF-? signalling in fibroblasts, and downregulation of IDH1 increased cellular concentration of ?-ketoglutarate (?-KG) by accelerating glutamine metabolization. Interestingly, ?-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-? signalling. These findings demonstrated that metabolic enzyme IDH1 regulates TGF-? signalling by feedback mechanism through ?-KG and TGFBR-IDH1-Cav1 axis is important for TGF-? signalling.

SUBMITTER: Hou X

PROVIDER: S-EPMC5663568 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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TGFBR-IDH1-Cav1 axis promotes TGF-β signalling in cancer-associated fibroblast.

Hou Xiaodan X Zhang Jieying J Wang Yongbin Y Xiong Wujun W Mi Jun J

Oncotarget 20170913 48

TGF-β signalling plays an important role in fibroblasts activation and tumour progression. Here, we report that the TGFBR-IDH1-Cav1 axis promotes TGF- β signalling in fibroblasts. Our data demonstrated that IDH1 was downregulated by TGF-β signalling in fibroblasts, and downregulation of IDH1 increased cellular concentration of α-ketoglutarate (α-KG) by accelerating glutamine metabolization. Interestingly, α-KG suppressed Cav1 expression through reducing the trimethylation of histone H3K4. Furthe ...[more]

PMID: 29137396

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Project description:BackgroundThe Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development.MethodsMKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis.ResultsMKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-β (TGF-β) signalling, and MKRN1 promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group.ConclusionsHigh MKRN1 levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC.

Dataset Information

TGFBR-IDH1-Cav1 axis promotes TGF-? signalling in cancer-associated fibroblast.

Publications

TGFBR-IDH1-Cav1 axis promotes TGF-β signalling in cancer-associated fibroblast.

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