Only humans and higher primates have high uric acid blood levels. Although high uric acid causes gout, it has been linked with human longevity because of its hypothetical antioxidant function. Recent studies reveal that p53 has significant roles in cellular metabolism. One example of this is an antioxidant function that potentially contributes to tumor suppression. Here, we reported a first beneficial link between p53 and uric acid. We identified the uric acid transporter SLC2A9 (also known as GLUT9) as a direct p53 target gene and a key downstream effector in the reduction of reactive oxygen species (ROS) through transporting uric acid as a source of antioxidant. Oxidative stress induced SLC2A9 expression in a p53-dependent manner, and inhibition of SLC2A9 by small interfering RNA (siRNA) or anti-gout drugs such as probenecid significantly increased ROS levels in an uric acid-dependent manner and greatly sensitized cancer cells to chemotherapeutic drugs. Conversely, expression of SLC2A9 reduced ROS and protected against DNA damage and cell death, suggesting its antioxidant function. The increased production of ROS because of p53 loss was rescued by SLC2A9 expression. Furthermore, decreased SLC2A9 expression was observed in several cancer types and was associated with a poorer prognosis. Our findings suggest that the p53-SLC2A9 pathway is a novel antioxidant mechanism that uses uric acid to maintain ROS homeostasis and prevent accumulation of ROS-associated damage that potentially contributes to cancer development.
Purpose: DZNep (3-deazaneplanocin A) depletes EZH2, a critical component of polycomb repressive complex 2 (PRC2), which is frequently deregulated in cancer. Despite exhibiting promising anticancer activity, the specific genetic determinants underlying DZNep responsiveness in cancer cells remain largely unknown. We sought to determine molecular factors influencing DZNep response in gastric cancer.Experimental Design: Phenotypic effects of DZNep were evaluated in a panel of gastric cancer cell lines. Sensitive lines were molecularly interrogated to identify potential predictors of DZNep responsiveness. The functional importance of candidate predictors was evaluated using short hairpin RNA (shRNA) and siRNA technologies.Results: DZNep depleted PRC2 pathway components in almost all gastric cancer lines, however, only a subset of lines exhibited growth inhibition upon treatment. TP53 genomic status was significantly associated with DZNep cellular responsiveness, with TP53 wild-type (WT) lines being more sensitive (P < 0.001). In TP53-WT lines, DZNep stabilized p53 by reducing ubiquitin conjugation through USP10 upregulation, resulting in activation of canonical p53 target genes. TP53 knockdown in TP53-WT lines attenuated DZNep sensitivity and p53 target activation, showing the functional importance of an intact p53 pathway in regulating DZNep cellular sensitivity. In primary human gastric cancers, EZH2 expression was negatively correlated with p53 pathway activation, suggesting that higher levels of EZH2 may repress p53 activity.Conclusion: Our results highlight an important role for TP53 genomic status in influencing DZNep response in gastric cancer. Clinical trials evaluating EZH2-targeting agents such as DZNep should consider stratifying patients with gastric cancer by their TP53 genomic status.
Activation of Wnt signaling due to Wnt overexpression or mutations of Wnt pathway components is associated with various cancers. Blocking Wnt secretion by inhibiting PORCN enzymatic activity has shown efficacy in a subset of cancers with elevated Wnt signaling. Predicting response to upstream Wnt inhibitors and monitoring response to therapeutics is challenging due to the paucity of well-defined biomarkers. In this study we identify Notum as a potential biomarker for Wnt driven cancers and show that coordinate regulation of NOTUM and AXIN2 expression may be a useful predictor of response to PORCN inhibitors. Most importantly, as NOTUM is a secreted protein and its levels in blood correlate with tumor growth, it has potential as a pharmacodynamic biomarker for PORCN and other Wnt pathway inhibitors.
<div>Abstract<p><b>Purpose:</b> DZNep (3-deazaneplanocin A) depletes EZH2, a critical component of polycomb repressive complex 2 (PRC2), which is frequently deregulated in cancer. Despite exhibiting promising anticancer activity, the specific genetic determinants underlying DZNep responsiveness in cancer cells remain largely unknown. We sought to determine molecular factors influencing DZNep response in gastric cancer.</p><p><b>Experimental Design:</b> Phenotypic effects of DZNep were evaluated in a panel of gastric cancer cell lines. Sensitive lines were molecularly interrogated to identify potential predictors of DZNep responsiveness. The functional importance of candidate predictors was evaluated using short hairpin RNA (shRNA) and siRNA technologies.</p><p><b>Results:</b> DZNep depleted PRC2 pathway components in almost all gastric cancer lines, however, only a subset of lines exhibited growth inhibition upon treatment. <i>TP53</i> genomic status was significantly associated with DZNep cellular responsiveness, with <i>TP53</i> wild-type (WT) lines being more sensitive (<i>P</i> < 0.001). In <i>TP53</i>-WT lines, DZNep stabilized p53 by reducing ubiquitin conjugation through USP10 upregulation, resulting in activation of canonical p53 target genes. <i>TP53</i> knockdown in <i>TP53</i>-WT lines attenuated DZNep sensitivity and p53 target activation, showing the functional importance of an intact p53 pathway in regulating DZNep cellular sensitivity. In primary human gastric cancers, <i>EZH2</i> expression was negatively correlated with p53 pathway activation, suggesting that higher levels of EZH2 may repress p53 activity.</p><p><b>Conclusion:</b> Our results highlight an important role for <i>TP53</i> genomic status in influencing DZNep response in gastric cancer. Clinical trials evaluating EZH2-targeting agents such as DZNep should consider stratifying patients with gastric cancer by their <i>TP53</i> genomic status. <i>Clin Cancer Res; 18(15); 4201–12. ©2012 AACR</i>.</p></div>
<div>Abstract<p><b>Purpose:</b> DZNep (3-deazaneplanocin A) depletes EZH2, a critical component of polycomb repressive complex 2 (PRC2), which is frequently deregulated in cancer. Despite exhibiting promising anticancer activity, the specific genetic determinants underlying DZNep responsiveness in cancer cells remain largely unknown. We sought to determine molecular factors influencing DZNep response in gastric cancer.</p><p><b>Experimental Design:</b> Phenotypic effects of DZNep were evaluated in a panel of gastric cancer cell lines. Sensitive lines were molecularly interrogated to identify potential predictors of DZNep responsiveness. The functional importance of candidate predictors was evaluated using short hairpin RNA (shRNA) and siRNA technologies.</p><p><b>Results:</b> DZNep depleted PRC2 pathway components in almost all gastric cancer lines, however, only a subset of lines exhibited growth inhibition upon treatment. <i>TP53</i> genomic status was significantly associated with DZNep cellular responsiveness, with <i>TP53</i> wild-type (WT) lines being more sensitive (<i>P</i> < 0.001). In <i>TP53</i>-WT lines, DZNep stabilized p53 by reducing ubiquitin conjugation through USP10 upregulation, resulting in activation of canonical p53 target genes. <i>TP53</i> knockdown in <i>TP53</i>-WT lines attenuated DZNep sensitivity and p53 target activation, showing the functional importance of an intact p53 pathway in regulating DZNep cellular sensitivity. In primary human gastric cancers, <i>EZH2</i> expression was negatively correlated with p53 pathway activation, suggesting that higher levels of EZH2 may repress p53 activity.</p><p><b>Conclusion:</b> Our results highlight an important role for <i>TP53</i> genomic status in influencing DZNep response in gastric cancer. Clinical trials evaluating EZH2-targeting agents such as DZNep should consider stratifying patients with gastric cancer by their <i>TP53</i> genomic status. <i>Clin Cancer Res; 18(15); 4201–12. ©2012 AACR</i>.</p></div>
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