NDRG2 is already known as a tumor suppressor, is involved in energy metabolism, especially glycosemetabolism(25, 26). In this study, the mRNA and protein expression levels of NDRG2 were analyzed in liver carcinoma tissues or non-carcinoma tissues, the results reconfirmed its down-expression in liver tumors (Fig. 1).
Recently, NDRG2 was involved in cellular glucose metabolism through insulin signal transduction based on the reports that NDRG2 is a substrate of kinase Akt and SGK1 (serum- and glucocorticoid-induced kinase 1)(27, 28). According to the Warburg effect, cancer cells are more prone to glycolysis than oxidative phosphorylation for glucose metabolism(29, 30). Glycolysis contributes to cancer progression(29), and glycolysis inhibition is emerging as a promising area of cancer therapy(31). Up to now, including in our study, NDRG2 has been shown to significantly inhibit glycolysis of tumor cells in colorectal cancer(10, 11), ccRCC(12), and liver cancer (Fig. 3C-F). In the light of these reports, the suppression of glycolysis by NDRG2 is the result of the regulation of glycolysis-related genes. Detailly, NDRG2 was firstly identified in breast cancer to decrease glucose uptake via promoting GLUT1 protein degradation without affecting GLUT1 transcription(32). Subsequently, the expression of glycolysis-related hexokinase 2 (HK2), pyruvate kinase M2 isoform (PKM2), and lactate dehydrogenase A (LDHA) were proved to be significantly suppressed by NDRG2 in colorectal cancer cells and ccRCC cells (10, 12). Moreover, NDRG2 could stimulate the TXINP expression to reduce glucose uptake(11).
Interestingly, although NDRG2 is named as an N-Mycdownstream-regulated gene it is not repressed by transcription factor N-Myc but by C-Myc(10, 33). C-Myc is known as a viral oncogene in cancer energy metabolism(34, 35) and mainly promotes glycolysis of cancer cells through up-regulating glycolysis genes expressions, such as LDH, HK2, GLUT1, and PKM2 (3). In addition, HIF-1 and P53, the two other transcription factors, also play crucial parts in tumorigenesis, could regulate the expression of glycolytic genes(36). HIF-1 promotes but P53 hinders these genes' expression(37, 38). Moreover, HIF-1 and P53 show negative and positive regulatory effects on NDRG2, respectively(39–42). Hence, we believe that the regulation of NDRG2 on glycolysis flux is accomplished by cooperating with C-Myc, HIF-1, and P53 to regulate the expression of glycolytic genes.
Sirtuins(SIRT1-7) play important roles in the Warburg effect and can regulate the glycolytic genes through their various effects(21). Sirtuins could directly regulate the expression of glycolytic enzymes, alter the enzymatic activity of glycolytic genes via multiple post-translational modifications and affect the sub-location of these enzymes(19, 21, 43, 44). For example, SIRT1was shown to promote the expression of GLUT1, GAPDH, and LDHA to benefit glycolysis(19, 43), interact with GAPDH, and keep it in the cytosol and thus promoting glycolysis expression(22). NDRG2 and SIRT1 showed opposite regulatory effects on the glycolytic enzyme, and this result may be due to the negative regulation of SIRT1 by NDRG2 (Fig. 4B-4C). The regulatory effects between SIRT1 and glycolytic regulators are opposite to that between NDRG2 and glycolytic regulators. The expression of SIRT1 increases through the C-Myc binding to the SIRT1 promoter, and then deacetylate C-Myc, and then stimulate the transcriptional activity of C-Myc(21); SIRT1-mediated deacetylation suppresses the functions of P53 (45). Overall, ndrg2 and sirt1, as a pair of negative regulatory genes, are opposite in the regulation of tumor glycolysis.