NTAQ1 Promotes Hepatocellular Carcinoma Growth by Facilitating the Protein Degradation of the Tumor Suppressor PRDM2

Abstract

Recent studies have demonstrated the crucial role of the arginine/N-degron pathway, which mediates protein degradation, in cancer initiation and progression. N-terminal glutamine amidohydrolase 1 (NTAQ1), an upstream enzyme in this pathway that catalyzes the deamidation of N-terminal glutamine residues, remains poorly understood in tumor biology. This study aimed to investigate the clinical significance and molecular functions of NTAQ1 in hepatocellular carcinoma (HCC). Copy number variation analysis using The Cancer Genome Atlas identified NTAQ1 as a potential driver of HCC progression. The biological role of NTAQ1 in HCC was investigated using in vitro experiments involving NTAQ1 overexpression (OE) in HCC cell lines. NTAQ1, located on the amplified chromosome 8q, exhibited elevated expression in the HCC tissues. NTAQ1 was also identified as an independent poor prognostic factor in patients with HCC, and immunohistochemical staining revealed that it primarily localized in the cytoplasm and membranes of HCC cells. NTAQ1 OE promoted HCC colony formation. Through in silico analysis, the tumor suppressor gene PR/SET Domain 2 (PRDM2) was identified to have a strong inverse correlation with NTAQ1 at the protein level. In vitro assays revealed that NTAQ1 OE enhanced PRDM2 degradation. Furthermore, NTAQ1 OE reduced DNA repair and apoptosis through decreased PRDM2 expression. In conclusion, NTAQ1 was identified as a novel driver gene in HCC that accelerates tumor growth by promoting degradation of the PRDM2 protein, thereby impairing DNA repair and suppressing apoptosis. These findings indicate that NTAQ1 could be a valuable target for treating HCC.