| First Author | Ren X | Year | 2022 |
| Journal | Cancer Res | Volume | 82 |
| Issue | 1 | Pages | 60-74 |
| PubMed ID | 34764205 | Mgi Jnum | J:317335 |
| Mgi Id | MGI:6852626 | Doi | 10.1158/0008-5472.CAN-21-1020 |
| Citation | Ren X, et al. (2022) The Protein Kinase Activity of NME7 Activates Wnt/beta-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma. Cancer Res 82(1):60-74 |
| abstractText | Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/beta-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/beta-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/beta-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3beta to promote beta-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of beta-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, beta-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/beta-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC. SIGNIFICANCE: The identification of NME7 as an activator of Wnt/beta-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease. |
