Abstract
Overexpression of fibroblast growth factor receptor 3 (FGFR3) correlates with more severe clinical features of hepatocellular carcinoma (HCC). Our previous study has shown that FGFR3∆7–9, a novel splicing mutation of FGFR3, contributes significantly to HCC malignant character, but the epigenetic mechanism is still elusive. In this study, through mass spectrometry and co-immunoprecipitation studies, we discover a close association between FGFR3∆7–9 and the DNA demethylase Ten-Eleven Translocation-2 (TET2). Unlike other certain types of cancer, mutation of TET2 is rare in HCC. However, activation of FGFR3∆7–9 by FGF1 dramatically shortens TET2 half-life. FGFR3∆7–9, but not wild-type FGFR3, directly interacts with TET2 and phosphorylates TET2 at Y1902 site, leading to the ubiquitination and proteasome-mediated degradation of TET2. Overexpression of a phospho-deficient mutant TET2 (Y1902F) significantly reduces the oncogenic potential of FGFR3∆7–9 in vitro and in vivo. Furthermore, FGFR3∆7–9 significantly enhances HCC cell proliferation through the TET2-PTEN-AKT pathway. Specifically, TET2 offsets the elevation of p-AKT level induced by FGFR3∆7–9 through directly binding to PTEN promoter and increasing 5-hmC. Therefore, through phosphorylation and inhibition of TET2, FGFR3∆7–9 reduces PTEN expression and substantiates AKT activation to stimulate HCC proliferation. Together, this study identifies TET2 as a key regulator of the oncogenic role of FGFR3∆7–9 in HCC carcinogenesis and sheds light on new therapeutic strategies for HCC treatment.
Highlights
Liver cancer is one of the most common cancers, and is the fourth lethal malignancy worldwide[1]
In a co-immunoprecipitation assay with ectopically expressed FGFR3Δ7–9 and Ten-Eleven Translocation-2 (TET2), we found that HA-tagged FGFR3Δ7–9 could precipitate mycTET2 from transfected 293T cells (Fig. 1a)
The physical interaction between TET2 and FGFR3Δ7–9 was supported by experiments conducted in an hepatocellular carcinoma (HCC) cell line (SMMC-7721) stably expressing fibroblast growth factor receptor 3 (FGFR3) (WT) or FGFR3Δ7–9
Summary
Liver cancer is one of the most common cancers, and is the fourth lethal malignancy worldwide[1]. The incidence of liver cancer continues to increase by 2 to 3% annually during 2007–2016 in United States[2]. Both genetic and epigenetic alterations play critical roles in HCC. We have shown that FGFR3Δ7–9, a novel mutant transcript, links exon 6 to exon 10 directly and promotes the proliferation, migration, and metastasis of HCC cells both in vitro and in vivo[4]. DNA methylation, which occurs mainly on the 5th carbon atom of cytosine (5-methylcytosine, 5-mC) in the context of CpG islands, has an important role in normal development and tumor development[5]. DNA methylation and demethylation are important for regulating chromosome structure, as well as gene expression.
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