Abstract
The fibroblast growth factor receptor 2 (FGFR2) is a membrane receptor that promotes cell proliferation and differentiation. FGFR2 is also present in the nucleus, which raises a question on a new role of FGFR2 in regulating gene expression. Hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2) are nuclear proteins that transactivate many genes essential for cancer survival and metastasis under hypoxic conditions. Here, we investigated if nuclear FGFR2 modulates the HIF-driven hypoxic response. Using the TCGA database, we found that FGFR2 downregulation is associated with poor prognosis in prostate cancer. A gene-set enrichment analysis showed that metastasis- and hypoxia-related genes are associated with a low expression of FGFR2 in prostate cancer. Thus, we tested the possibility that FGFR2 negatively regulates the hypoxia-triggered metastasis of prostate cancer. FGFR2 controls migration and invasion of prostate cancer cells under hypoxia by inhibiting the HIF-driven gene expression. FGFR2 and HIF proteins co-localize and associate in the nucleus under hypoxia. FGFR2 interacts with the transactivation domain of HIF-1α and blocks the recruitment of coactivator p300, resulting in repression of HIF target genes. Based on these results, we propose a novel function of FGFR2 as a metastasis suppressor by controlling HIF-mediated hypoxic responses.
Highlights
PER-ARNT-SIM (PAS) domain family of transcription factors, are essential for cell survival in oxygen deficiency
We further demonstrated that fibroblast growth factor receptor 2 (FGFR2) negatively regulates cancer cell invasion under hypoxia and its expression is inversely correlated with prostate cancer progression
Informatics analyses revealed that a low expression of FGFR2 mRNA was significantly associated with poor prognosis in prostate adenocarcinoma, cervical squamous cell carcinoma, and glioblastoma multiforme (Fig. 1a, Supplementary Fig. 1)
Summary
PER-ARNT-SIM (PAS) domain family of transcription factors, are essential for cell survival in oxygen deficiency. Factor Inhibiting HIF (FIH) hydroxylates an asparagine residue on the C-terminal transactivation domain of HIF-1/2α, which prevents the binding of the cofactors p300/CBP to HIF-1/2α, thereby inhibiting the HIF-driven transcription[5] As these hydroxylases utilize O2 as a co-substrate, HIF-1/2α become stable and active under O2-deficient conditions. Upon binding with FGF, the receptors form homodimer complexes and their kinase domains are activated These receptors trigger the activation of their signaling cascades, such as AKT, RAS, and IP3 pathways, resulting in enhanced cell proliferation, differentiation and so on[8]. FGFR2 has been reported to interact with the transcriptional factor Signal transducer and activator of transcription 5 (STAT5) in the nucleus and to act as a transcriptional coactivator[13] These reports prompted us to a new hypothesis that nuclear FGFR2 acts as a co-modulator for the HIF-driven expression of hypoxia-related genes. In a view of molecular mechanism, the roles of FGFRs in hypoxic responses have not been intensively investigated so far
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