Abstract
PRL-3, an oncogenic dual-specificity phosphatase, is overexpressed in 50% of acute myelogenous leukemia (AML) and associated with poor survival. We found that stable expression of PRL-3 confers cytokine independence and growth advantage of AML cells. However, how PRL-3 mediates these functions in AML is not known. To comprehensively screen for PRL3-regulated proteins in AML, we performed SILAC-based quantitative proteomics analysis and discovered 398 significantly perturbed proteins after PRL-3 overexpression. We show that Leo1, a component of RNA polymerase II-associated factor (PAF) complex, is a novel and important mediator of PRL-3 oncogenic activities in AML. We described a novel mechanism where elevated PRL-3 protein increases JMJD2C histone demethylase occupancy on Leo1 promoter, thereby reducing the H3K9me3 repressive signals and promoting Leo1 gene expression. Furthermore, PRL-3 and Leo1 levels were positively associated in AML patient samples (N=24; P<0.01). On the other hand, inhibition of Leo1 reverses PRL-3 oncogenic phenotypes in AML. Loss of Leo1 leads to destabilization of the PAF complex and downregulation of SOX2 and SOX4, potent oncogenes in myeloid transformation. In conclusion, we identify an important and novel mechanism by which PRL-3 mediates its oncogenic function in AML.
Highlights
PRL-3, encoded by the PTP4A3 gene, is a small dualspecificity phosphatase characterized by the conserved C(X5)R catalytic domain, and a unique C-terminal prenylation domain essential for its proper subcellular localization [1, 2]
We found that PRL-3 has pro-oncogenic properties in acute myelogenous leukemia (AML), and Leo1, a component of the human RNA polymerase II–associated factor (PAF) complex, is one of the most differentially expressed proteins induced by PRL-3
To assess the roles of PRL-3 in pathogenesis of AML, we developed a pair of stable, isogenic cell lines, TF1-pEGFP and TF1-hPRL3 by transfecting pEGFP and pEGFP-hPRL-3 vectors into TF-1 cells, respectively, followed by G418 selection and fluorescence-activated cell sorting (Fig. 1A)
Summary
PRL-3, encoded by the PTP4A3 gene, is a small dualspecificity phosphatase characterized by the conserved C(X5)R catalytic domain, and a unique C-terminal prenylation domain essential for its proper subcellular localization [1, 2]. PRL-3 has been shown to promote cellular processes, such as cell motility, invasion, cell growth, and survival, through various mechanisms [2,3,4,5,6,7]. PRL-3 was first linked to cancer when it was consistently found at elevated levels in colorectal cancer metastases, but at much lower levels in matched early-staged tumor and normal colorectal epithelium [8]. Since elevated expression of PRL-3 has been implicated in the progression and metastasis of an array of cancer types, including gastric, ovarian, cervical, lung, liver, Authors' Affiliations: 1Cancer Science Institute of Singapore; 2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; 3Department of Biological Sciences, Nanyang Technological University; 4Institute of Molecular and Cell Biology (AÃSTAR); and 5Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
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