Data from Loss of Glycogen Debranching Enzyme AGL Drives Bladder Tumor Growth via Induction of Hyaluronic Acid Synthesis

Abstract

<div>Abstract<p><b>Purpose:</b> We demonstrated that amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL) is a tumor growth suppressor and prognostic marker in human bladder cancer. Here we determine how AGL loss enhances tumor growth, hoping to find therapeutically tractable targets/pathways that could be used in patients with low AGL–expressing tumors.</p><p><b>Experimental Design:</b> We transcriptionally profiled bladder cell lines with different AGL expression. By focusing on transcripts overexpressed as a function of low AGL and associated with adverse clinicopathologic variables in human bladder tumors, we sought to increase the chances of discovering novel therapeutic opportunities.</p><p><b>Results:</b> One such transcript was hyaluronic acid synthase 2 (<i>HAS2</i>), an enzyme responsible for hyaluronic acid (HA) synthesis. <i>HAS2</i> expression was inversely proportional to that of AGL in bladder cancer cells and immortalized and normal urothelium. HAS2-driven HA synthesis was enhanced in bladder cancer cells with low AGL, and this drove anchorage-dependent and independent growth. siRNA-mediated depletion of HAS2 or inhibition of HA synthesis by 4-methylumbelliferone (4MU) abrogated <i>in vitro</i> and xenograft growth of bladder cancer cells with low AGL. <i>AGL</i> and <i>HAS2</i> mRNA expression in human tumors was inversely correlated in patient datasets. Patients with high <i>HAS2</i> and low <i>AGL</i> tumor mRNA expression had poor survival, lending clinical support to xenograft findings that HAS2 drives growth of tumors with low AGL.</p><p><b>Conclusions:</b> Our study establishes HAS2-mediated HA synthesis as a driver of growth of bladder cancer with low AGL and provides preclinical rationale for personalized targeting of HAS2/HA signaling in patients with low AGL–expressing tumors. <i>Clin Cancer Res; 22(5); 1274–83. ©2015 AACR</i>.</p></div>