Aiello A, Pandini G, Sarfstein R, Werner H, Manfioletti G, Vigneri R, Belfiore A

The IGF-I receptor (IGF-IR) is often overexpressed in cancer and is believed to play a crucial role in cancer progression. High Mobility Group A1 (HMGA1) is a non-histone chromatin protein that has the ability to regulate gene expression through DNA binding and involvement in enhanceosome complexes. HMGA1 is expressed at ...

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low level in adult differentiated cells, whereas it is expressed at high level in embryonic and malignant cells. We evaluated whether the HMGA1 aberrant expression has a role in IGF-IR overexpression in cancer. We found that HMGA1 silencing induces a marked decrease in IGF-IR expression in various human cancer cell lines. Conversely, forced HMGA1 overexpression in cells with low endogenous HMGA1 levels was associated with IGF-IR upregulation. HMGA1 silencing reduced igf-ir promoter activity whereas forced HMGA1 expression increased it. Using the chromatin immunoprecipitation assay, HMGA1 protein was found to bind to the igf-ir promoter. Moreover, HMGA1 was found to associate with both p53 and Sp1, two major regulators of igf-ir gene transcription and to antagonise the p53 inhibitory activity while enhancing the Sp1 stimulatory activity. Our data indicate, therefore, that HMGA1 protein is a positive regulator of IGF-IR expression and that HMGA1 overexpression may contribute to IGF-IR dysregulation in cancer cells.

Date: Jul. 01, 2010

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