Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells
| Autor: | Travis J. Jerde, Peter C. Hollenhorst, Brady G. Strittmatter |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Cancer Research genetic structures Carcinogenesis Gene Expression QH426-470 Biochemistry Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Movement Genes Regulator Medicine and Health Sciences Post-Translational Modification Phosphorylation Extracellular Signal-Regulated MAP Kinases Genetics (clinical) Regulation of gene expression Chromosome Biology Prostate Cancer EZH2 Prostate Diseases Prostate Chromatin Cell biology Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Oncology 030220 oncology & carcinogenesis Heterografts Epigenetics Anatomy Erg Research Article Signal Transduction Transcriptional Activation Epithelial-Mesenchymal Transition MAP Kinase Signaling System Urology Mice Nude Biology 03 medical and health sciences Exocrine Glands Transcriptional Regulator ERG Cell Line Tumor Genetics Animals Humans Gene Regulation Epithelial–mesenchymal transition Molecular Biology Protein kinase B Transcription factor Ecology Evolution Behavior and Systematics PI3K/AKT/mTOR pathway Cancers and Neoplasms Biology and Life Sciences Proteins Prostatic Neoplasms Cell Biology eye diseases Genitourinary Tract Tumors 030104 developmental biology ras Proteins Prostate Gland sense organs Proto-Oncogene Proteins c-akt Transcription Factors |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 17, Iss 7, p e1009708 (2021) |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1009708 |
| Popis: | The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function. Author summary ERG is the most common oncogene in prostate cancer. The ERG protein can bind DNA and can activate some genes and repress others. Previous studies indicated that ERG cannot promote cancer by itself, but that ERG works together with mutations that activate the protein AKT. In this study we found that activation of AKT changes the genes that ERG regulates, leading to luminal epithelial differentiation, which is a hallmark of most prostate tumors. However, we also found that a mutant version of ERG that can activate, but cannot repress genes, can drive prostate tumorigenesis without activation of AKT, but this mutant ERG cannot promote luminal differentiation. Our findings suggest that ERG mediated tumorigenesis only requires ERG’s activation function and can occur independent of luminal cell differentiation. |
| Databáze: | OpenAIRE |
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