Metabolic reprogramming is a hallmark of cancer. Glycine decarboxylase (GLDC)， an oxidoreductase， plays an important role in amino acid metabolism. While GLDC promotes tumor initiation and proliferation in non-small cell lung cancer and glioma and it was reported as a putative tumor suppressor gene in gastric cancer， the role of GLDC in hepatocellular carcinoma (HCC) is unknown. In the current study， microarray-based analysis suggested that GLDC expression was low in highly malignant HCC cell lines， and clinicopathological analysis revealed a decrease in GLDC in HCC tumor samples. While the knockdown of GLDC enhanced cancer cell migration and invasion， GLDC overexpression inhibited them. Mechanistic... More
Metabolic reprogramming is a hallmark of cancer. Glycine decarboxylase (GLDC)， an oxidoreductase， plays an important role in amino acid metabolism. While GLDC promotes tumor initiation and proliferation in non-small cell lung cancer and glioma and it was reported as a putative tumor suppressor gene in gastric cancer， the role of GLDC in hepatocellular carcinoma (HCC) is unknown. In the current study， microarray-based analysis suggested that GLDC expression was low in highly malignant HCC cell lines， and clinicopathological analysis revealed a decrease in GLDC in HCC tumor samples. While the knockdown of GLDC enhanced cancer cell migration and invasion， GLDC overexpression inhibited them. Mechanistic studies revealed that GLDC knockdown increased the levels of reactive oxygen species (ROS) and decreased the ratio of glutathione/oxidized glutathione (GSH/GSSG)， which in turn dampened the ubiquitination of cofilin， a key regulator of actin polymerization. Consequently， the protein level of cofilin was elevated， which accounted for the increase in cell migration. The overexpression of GLDC reversed the phenotype. Treatment with N-acetyl-L-cysteine decreased the protein level of cofilin while treatment with HO increased it， further confirming the role of ROS in regulating cofilin degradation. In a tumor xenographic transplant nude mouse model， the knockdown of GLDC promoted intrahepatic metastasis of HCC while GLDC overexpression inhibited it. Our data indicate that GLDC downregulation decreases ROS-mediated ubiquitination of cofilin to enhance HCC progression and intrahepatic metastasis.
