Involvement of glycogen debranching enzyme in bladder cancer

Abstract

Bladder cancer is the most common malignancy of the urinary system, however the molecular pathways underlying this disease are incompletely understood. To understand new regulators of bladder cancer progression, the authors carried out a functional genomic screen which identified glycogen debranching enzyme (AGL) as a novel regulator of bladder cancer growth. Glycogen debranching enzyme is involved in glycogen breakdown and germline loss of function mutation of this gene leads to glycogen storage disease type III. To the best of the authors' knowledge, the present study is the first to demonstrate that loss of AGL leads to aggressive bladder tumor growth. AGL mRNA and protein expression in bladder tumors serve as a prognostic marker for patients. Interestingly, AGL's participation in regulating tumor growth is independent of its enzymatic function and involvement with glycogen metabolism in general. Detailed metabolomics and transcriptomic analysis indicated that increases in glucose metabolism, glycine synthesis driven by serine hydroxymethyltransferase 2 and increases in hyaluronic acid synthase 2-driven HA synthesis are major contributors of aggressive bladder tumor growth with loss of AGL. However, the detailed mechanism of how AGL regulates the above mentioned metabolic and genetic pathways is unknown and is being investigated. The present review focuses on AGL's involvement in bladder cancer.

Keywords: CD44; HAS2; RHAMM; SHMT2; bladder cancer; glycogen debranching enzyme; hyaluronic acid.

Figure 1.

Signaling pathways affected by loss of AGL expression resulting in aggressive growth of bladder tumors. Loss of AGL leads to overexpression of SHMT2 and HAS2, which results in increased glycine and HA synthesis, respectively. This increase in glycine and HA synthesis is supported by increased glucose uptake and metabolism by these cells. Increased glycine synthesis promotes rapid cell proliferation by increasing nucleotide synthesis and increase in HA synthesis promotes tumor growth by signaling through its receptors, CD44 and RHAMM. AGL, glycogen debranching enzyme; SHMT2, hydroxymethyltransferase 2; HAS2, hyaluronic acid synthase 2; RHAMM, hyaluronan mediated motility receptor.