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Gene Expression Profiling Reveals Regulation of ERK Phosphorylation by Androgen-Induced Tumor Suppressor U19/EAF2 in the Mouse Prostate

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Cancer Microenvironment

Abstract

U19/EAF2 is regulated by androgens in the prostate and capable of regulating transcriptional elongation of RNA Pol II via interaction with the ELL family proteins. Inactivation of U19/EAF2 induces tumorigenesis in multiple organs; however the mechanism of U19/EAF2 tumor suppression remains unclear. To elucidate potential mechanisms of U19/EAF2 action, we performed cDNA microarray analysis and identified 164 mRNA transcripts regulated by U19/EAF2 in the mouse ventral prostate. Bioinformatics analysis indicated that U19/EAF2 knockout activates the RAS-BRAF-ERK signaling pathway, which is known to play important roles in carcinogenesis. qPCR verified increased expression of BRAF mRNA, and immunostaining and Western blot analysis demonstrated increased expression of p-ERK at the protein level suggested U19/EAF2 knockout activates this important pathway. These findings indicate that loss of EAF2 up-regulates transcription of RAS cascade genes including Grb2, PI3K, and BRAF, leading to elevated p-ERK levels, which may represent a major functional role of U19/EAF2 in the prostate. Furthermore, these observations suggest that U19/EAF2 is a key player in crosstalk between androgen receptor and the RAS-BRAF-ERK signaling pathway.

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Acknowledgement

This study was supported in part by National Institutes of Health Grants R37 DK51193, R01 CA 108675, and P50 CA90386 and the Tippins Foundation (LEP). This project used the UPCI Animal Facility and was supported in part by award P30CA047904. We also thank Junkui Ai and Liquan Cai for critical reading.

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Author notes

  1. Fei Su

    Present address: Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, 77204, USA

Authors and Affiliations

  1. Department of Urology, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    Fei Su, Laura E. Pascal & Zhou Wang

  2. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    Jianhua Luo

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    Zhou Wang

  4. Department of Computing and Mathematics FFCLRP-USP, University of São Paulo, Ribeirão Preto, Brazil

    Bruna R. S. Correa & Ricardo Z. N. Vencio

  5. Department of Urology, University of Pittsburgh Cancer Institute, 5200 Centre Ave, Suite G40, Pittsburgh, PA, 15232, USA

    Zhou Wang

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  1. Fei Su
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  2. Bruna R. S. Correa
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Correspondence to Zhou Wang.

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Additional File 1

Functional categories enriched in differentially expressed genes in U19/EAF2 knockout ventral prostate. (XLS 51 kb)

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Su, F., Correa, B.R.S., Luo, J. et al. Gene Expression Profiling Reveals Regulation of ERK Phosphorylation by Androgen-Induced Tumor Suppressor U19/EAF2 in the Mouse Prostate. Cancer Microenvironment 6, 247–261 (2013). https://doi.org/10.1007/s12307-013-0132-4

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