The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways.
The transforming growth factor beta, Hedgehog, Notch, and Wnt signaling pathways all play critical roles in the development and progression of prostate cancer. It is becoming increasingly apparent that these pathways may intersect with developmentally important transcription factors such as the sex-determining region Y-box 4 (SOX4), homeobox C6, enhancer of zeste 2, and ETS-related gene, which are up-regulated in prostate cancers. For example, identification of the downstream targets of SOX4 and homeobox C6 suggests that these factors may cooperate to activate the Notch pathway and the PI3K/AKT pathway, possibly in response to Wnt signals. PI3K/AKT activation likely occurs indirectly via up-regulation of growth factor receptors, while Notch activation is secondary to up-regulation of Notch pathway components. In addition, SOX4 may affect terminal differentiation via regulation of other transcription factors such as NKX3.1 and MLL, and regulation of components of the microRNA pathway such as Dicer and Argonaute 1. The evidence supporting activation of these pathways in prostate cancer progression suggests that combinations of compounds targeting them may be of benefit to patients with aggressive, metastatic disease.
Moreno
Carlos S
CS
Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Atlanta, GA 30322, USA. cmoreno@emory.edu
D001363:Awards and Prizes; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020239:Receptor Cross-Talk / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism / Q000502:physiology; D055751:SOXC Transcription Factors / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology
D018398:Homeodomain Proteins; D051880:Receptors, Notch; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D051153:Wnt Proteins; D019869:Phosphatidylinositol 3-Kinases