Data from <i>TP53</i> Genomic Status Regulates Sensitivity of Gastric Cancer Cells to the Histone Methylation Inhibitor 3-Deazaneplanocin A (DZNep)

Abstract

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; 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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; 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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; DZNep depleted PRC2 pathway components in almost all gastric cancer lines, however, only a subset of lines exhibited growth inhibition upon treatment. &lt;i&gt;TP53&lt;/i&gt; genomic status was significantly associated with DZNep cellular responsiveness, with &lt;i&gt;TP53&lt;/i&gt; wild-type (WT) lines being more sensitive (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). In &lt;i&gt;TP53&lt;/i&gt;-WT lines, DZNep stabilized p53 by reducing ubiquitin conjugation through USP10 upregulation, resulting in activation of canonical p53 target genes. &lt;i&gt;TP53&lt;/i&gt; knockdown in &lt;i&gt;TP53&lt;/i&gt;-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, &lt;i&gt;EZH2&lt;/i&gt; expression was negatively correlated with p53 pathway activation, suggesting that higher levels of EZH2 may repress p53 activity.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusion:&lt;/b&gt; Our results highlight an important role for &lt;i&gt;TP53&lt;/i&gt; 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 &lt;i&gt;TP53&lt;/i&gt; genomic status. &lt;i&gt;Clin Cancer Res; 18(15); 4201–12. ©2012 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;