Tumor suppressor NDRG2 tips the balance of oncogenic TGF-β via EMT inhibition in colorectal cancer

Abstract

Transforming growth factor-beta (TGF-β), a pluripotent cytokine expressed in the colon, has a crucial but paradoxical role in colorectal cancer (CRC). TGF-β is a potent proliferation inhibitor of normal colon epithelial cells and acts as a tumor suppressor. However, TGF-β also promotes invasion and metastasis during late-stage CRC, thereby acting as an oncogene. Thus, understanding the factors behind the paradoxical roles of TGF-β and elucidating the mechanisms by which TGF-β-induced proliferation inhibition is impaired in CRC are necessary. Here, we found that the N-Myc tumor suppressor gene downstream-regulated gene NDRG2 (N-Myc downstream-regulated gene 2), which is a TGF-β-responsive gene, abrogated TGF-β-induced epithelial–mesenchymal transition (EMT) and further inhibited the invasion and migration of CRC cells. TGF-β positively induced NDRG2 expression through direct transactivation mediated by Sp1 and by abrogation of the repressive c-Myc/Miz-1 complex on NDRG2 promoter in normal epithelial cells. Aberrant hypermethylation of NDRG2, which could respond to TGF-β growth inhibition signaling, abrogated the inhibitory effect of NDRG2 in TGF-β-induced EMT in CRCs. Reduced NDRG2 expression was highly correlated with the invasion stage and metastasis of CRC. Our study establishes that NDRG2 is a new tumor suppressor gene that responds to TGF-β anti-proliferative signaling and tips the balance of oncogenic TGF-β during late-stage CRC.

LIM and SH3 Protein 1 Induces TGFβ-Mediated Epithelial–Mesenchymal Transition in Human Colorectal Cancer by Regulating S100A4 Expression

“…Cancer cells undergoing EMT acquired invasive properties. Numerous studies have illustrated that EMT is a common molecular mechanism in colorectal cancer metastasis, and many proteins contribute to this process (21,22). Taking this into consideration, we hypothesized that LASP1 is involved in EMT-mediated colorectal cancer metastasis.…”

MicroRNA-486 Alleviates Hypoxia-Induced Damage in H9c2 Cells by Targeting NDRG2 to Inactivate JNK/C-Jun and NF-κB Signaling Pathways

“…In this study, NDRG2 was confirmed as a target of miR-486 and NDRG2 expression could be negatively regulated by miR-486. NDRG2 is proposed to be a tumor suppressor gene that plays a key role in the development of diverse human cancers [23][24][25][26]. Interestingly, a previous study had discovered that NDRG2 in the heart is modulated by myocardial I/R and may be involved in I/R-induced cardiac tissue injury [27].…”

β-Galactoside α2,6-Sialyltranferase 1 Promotes Transforming Growth Factor-β-mediated Epithelial-Mesenchymal Transition

“…However, in contrast to the case of vimentin, in which Sp1 and Smad together act as a switch for vimentin expression, these two transcription factors may function to regulate the St6gal1 expression independently, because deletion of the putative Smad binding sites within the St6gal1 promoter only decreased the efficiency of St6gal1 induction instead of completely abrogating its promoter activity. Recently, Sp1 and Smad proteins have been found to control the expression of tumor suppressor NDRG2 in a similar way during the TGF-␤-induced EMT (48). These observations raise the question of how this regulatory strategy of St6gal1/NDRG2 expression benefits the cells.…”