FOXP3, a novel glioblastoma oncosuppressor, affects proliferation and migration

The transcription factor FOXP3, a master regulator of Treg cells has been proposed to function as a tumor suppressor in breast and prostate cancer. In the present study we provide evidence that FOXP3 is expressed in normal brain but strongly down-regulated in both primary and recurrent glioblastoma (GB) specimens and in corresponding cell lines growing in culture in the presence of mitogenic factors (mostly Epidermal Growth Factor - EGF and b-Fibroblast Growth Factor – bFGF) as neurospheres (NS). We also found that FOXP3 expression was higher in low-grade gliomas than in GB. Neurosphere generation, a feature present in 58% of the GB that we examined, correlated with lower expression of FOXP3 and shorter patient survival. Our main result refers to the contribution of FOXP3 expression in affecting proliferation and migration in vitro and in vivo. FOXP3 was silenced in one GB-NS expressing measurable levels of the gene. Intracranial injection of these GB-NS cells in nude mouse brains increased significantly tumor development and aggressiveness. Deriving gliomas showed a total absence of FOXP3 expression associated with a significant increase in proliferation and migration. Conversely, FOXP3 over-expression impaired GB-NS migration and proliferation in vitro. We also demonstrated using ChIP that FOXP3 is a transcriptional regulator of p21 and c-MYC supporting the idea that dysregulated expression of these factors is a major mechanism of tumorigenesis driven by the loss of FOXP3 expression in gliomas. These findings support the assertion that FOXP3 exhibits tumor suppressor activity in glioblastomas.