Abstract
Prostate cancer is a major health issue in the Western world. The most common gene rearrangement in prostate cancer is the TMPRSS2-ERG fusion, which results in aberrant expression of the transcription factor ERG. The insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and tumorigenesis, and is overexpressed in most malignancies, including prostate cancer. In this study we show that TMPRSS2-ERG mediates its tumorigenic effects through regulation of IGF1R gene expression. Silencing of T-ERG in VCaP cells resulted in downregulation of both IGF1R and Sp1, a critical IGF1R regulator. Co-immunoprecipitation assays revealed a physical interaction between transcription factors ERG and Sp1, with potential relevance in IGF1R gene regulation. In addition, transactivation of the IGF1R gene by ERG was mediated at the level of transcription, as indicated by results of promoter assays. To identify new co-activators of the TMPRSS2-ERG fusion protein we performed mass spectrometry-based proteomic analyses. Among other interactors, we identified AP-2 complex subunit mu (AP2M1) and caveolin-1 (CAV1) in association with ERG in cell nuclei. These proteins play a mechanistic role in IGF1R internalization. Our analyses are consistent with a potential novel function of TMPRSS2-ERG as a major regulator of IGF1R gene expression. Results may impinge upon ongoing efforts to target the IGF1R in the clinics.
Highlights
The involvement of the insulin-like growth factor (IGF) axis in prostate cancer biology has been well established [1,2,3]
Results obtained revealed that (i) the fusion-encoded ERG oncogene is a potent trans-activator of the IGF1 receptor (IGF1R) gene; (ii) enhanced IGF1R expression is mediated at the level of IGF1R promoter transcription; and (iii) enhanced IGF1R expression leads to activation of cell-survival downstream signaling pathways
To investigate the potential effect of the TMPRSS2-ERG fusion protein on IGF1R gene expression, we employed two metastatic prostate cancer-derived cell lines with or without the chimera: the VCaP cell line, which expresses the chimeric protein in an endogenous manner, and the M12 cell line, which is devoid of the fusion protein
Summary
The involvement of the insulin-like growth factor (IGF) axis in prostate cancer biology has been well established [1,2,3]. While the normal function of TMPRSS2 is unknown, the TMPRSS2 gene has been identified as an androgenresponsive gene Fusion of this gene to members of the ETS family of transcription factors, in particular ERG or ETV1, leads to overexpression of the oncogenes in a large portion of prostate cancer cases, but not in benign prostate samples, in an androgen-dependent manner. In view of the role of fusion protein TMPRSS2ERG in prostate cancer and to expand our previous studies on the transcriptional regulation of the IGF1R gene, we examined the hypothesis that the IGF1R gene constitutes a novel downstream target for the TMPRSS2-ERG prostate-specific chimera. Results obtained revealed that (i) the fusion-encoded ERG oncogene is a potent trans-activator of the IGF1R gene; (ii) enhanced IGF1R expression is mediated at the level of IGF1R promoter transcription; and (iii) enhanced IGF1R expression leads to activation of cell-survival downstream signaling pathways. Using a mass spectroscopy proteomic approach we identified a series of ERG interactors that might be involved in ERG-mediated IGF1R transcription, processing and internalization
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