Abstract
Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies.
Highlights
A characteristic of many solid tumors is that they contain regions of low oxygen availability and express elevated levels of hypoxia inducible factors (HIFs) [1]
We demonstrated that aryl hydrocarbon receptor nuclear translocator (ARNT), thyroid hormone receptor/ retinoblastoma-interacting protein 230 (TRIP230) and retinoblastoma protein (Rb) form a complex and that Rb represses the function of TRIP230 and the transcriptional response to hypoxia [12]
vascular endothelial growth factor (VEGF) and CXCR4 mRNA accumulation in LNCaP-shSCX cells displayed typical hypoxia induction profiles, significantly exacerbated transcriptional responses occurred in LNCaP-shRb cells subjected to 24 hours of hypoxia when compared to scrambled controls (Figure 1C and 1D)
Summary
A characteristic of many solid tumors is that they contain regions of low oxygen availability (hypoxia) and express elevated levels of hypoxia inducible factors (HIFs) [1]. The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT/HIF1β), is the master regulator of the hypoxic response. HIFs accumulate, translocate to the nucleus, and bind ARNT [2]. The HIF1 complex binds to hypoxia response elements and recruits co-activators such as the thyroid hormone receptor/ retinoblastoma-interacting protein 230 (TRIP230) [3], CBP/p300 [4] and Brm/Brg-1 [5] to modulate the expression of genes. Typical HIF1-regulated genes include angiogenic and metabolic targets, such as vascular endothelial growth factor (VEGF) [6] and GLUT1 [7] and include metastatic markers, like CXCR4 [8] and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) [9]. The microenvironment of solid tumors is conducive to the activation of hypoxia-regulated genetic programs and these support tumor growth
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