Downregulation of N-myc downstream regulated gene 1 caused by the methylation of CpG islands of NDRG1 promoter promotes proliferation and invasion of prostate cancer cells

Abstract

Current studies tend to consider N-myc downstream regulated gene 1 (NDRG1) as a tumor suppressor gene, inhibiting cell proliferation and invasion. NDRG1 expression in cancer cells is generally low, but the molecular mechanism is unclear. Aberrant methylation of CpG islands (CGIs) in gene promoter was able to inactivate tumor suppressor genes and activate oncogenes, disordering cell proliferation and apoptosis, playing a promotion role in tumor occurrence and progression. The present study was performed to investigate the effect of epigenetic modification of NDRG1 on prostate cancer (PCa) cells. The protein expression in human specimens was measured by immunohistochemical staining. The expression level of NDRG1 was changed by plasmid vectors in PCa cells. These cells were used to study proliferation and invasiveness. NDRG1 expression in normal prostate cells was higher than that in PCa cells. Downregulation of NDRG1 expression enhanced cell proliferation and invasiveness. In contrast, its upregulation could reduce cell proliferation and invasiveness. In PCa cells, the methylation rate of CGIs in the promoter region of NDRG1 was higher than that in normal prostate cells. 5-Aza-CdR, a methylation inhibitor, was able to effectively reverse the aberrant methylation of NDRG1, enhancing its expression, inhibiting cell growth. NDRG1 can inhibit the cell proliferation and invasion of PCa, but its expression level is low. The aberrant methylation of NDRG1 promoter is an important mechanism for gene silencing, playing an important role in tumor occurrence and progression. Therefore, reversing the aberrant methylation of NDRG1 may be used for PCa treatment.

Triptolide exhibits antitumor effects by reversing hypermethylation of WIF‑1 in lung cancer cells

“…Thus, restoring normal WIF-1 expression may downregulate the Wnt signaling pathway and inhibit the progression of lung cancer. In human tumors, abnormal methylation of CpG islands in promoter regions results in a suppression of the transcriptional activity of tumor suppressor genes (35)(36)(37). Previous studies have demonstrated that numerous tumor suppressor genes associated with lung cancer are downregulated via methylation of the promoter region (23,35,38).…”

N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2

“…N-myc downstream-regulated gene 1 ( NDRG1 ) plays a potent role in modulating metastatic ability in multiple types of solid tumor including CRC [ 16 , 17 ], breast cancer [ 18 , 19 ] and prostate cancer [ 20 , 21 ]. Also, NDRG1 has been linked to many cellular processes including cell cycle, apoptosis, and cellular differentiation [ 22 – 26 ].…”

Unique targeting of androgen‐dependent and ‐independent AR signaling in prostate cancer to overcome androgen resistance

“…The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), was found to play an important role in PCa progression, being reduced in PCa compared to adjacent normal tissues. [5][6][7] Increasing NDRG1 expression in PCa cells had several effects, including the inhibition of (1) proliferation;…”

“…(2) the epithelial to mesenchymal transition (EMT), and (3) cell migration and invasion in vitro and metastasis in vivo. [5][6][7][8][9][10][11] NDRG1 also inhibits major oncogenic signaling pathways including EGFR and its downstream MAPK signaling, as well as the PI3K/AKT pathway in cancer cells. 10,12,13 Considering the role of NDRG1 in PCa, agents that can upregulate this protein could be highly efficacious against this disease.…”