Genistein inhibits invasion and migration of colon cancer cells by recovering WIF1 expression

Abstract

Colon cancer is characterized by invasion and migration. DNA methylation of CpG islands in tumor suppressor genes is considered to be an epigenetic mechanism underlying cancer development. Epigenetic silencing of a gene may be reversed by drugs, including genistein. The present study aimed to determine the effect of genistein on Wnt inhibitory factor 1 (WIF1) and invasion, and migration of colon cancer cells. The viability of HT29 colon cancer cells was suppressed by genistein in a dose dependent manner. Following 72 h of treatment with 10, 20 and 60 µmol/l genistein, increased demethylation of WIF1 was induced in a dose‑dependent manner. Additionally, the invasive/migratory abilities of cells treated with genistein decreased in a dose‑dependent manner. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were performed to identify the mRNA and protein expression levels of invasion/migration‑associated factors. Following treatment with genistein, matrix metalloproteinase (MMP) 2 and MMP9 expression levels decreased, whereas the expression of metalloproteinase inhibitor 1 and E‑cadherin increased significantly. In addition, the expression levels of proto‑oncogene Wnt‑1 (Wnt‑1)/β‑catenin pathway‑associated factors, β‑catenin, c‑Myc proto‑oncogene protein and cyclin D1 decreased in a dose‑dependent manner following treatment with genistein. The invasive/migratory abilities of cells transfected with WIF1‑small interfering (si) RNA, and those transfected with WIF1‑siRNA and treated with genistein, increased notably compared with the control group. The present study demonstrated that genistein was able to inhibit the cell invasion and migration of colon cancer cells by inducing demethylation, and recovering the activity of WIF1 by altering the expression of invasion‑associated factors, and components of the Wnt signaling pathway.

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“…NF-κB is induced by irradiation and is shown to promote proliferation through the activation of c-myc, which is a negative regulator of p21, p27, and GADD45a [52,53]. Genistein has also been shown to inhibit expression of NF-κB and c-myc [54][55][56]. Genistein may be promoting cell cycle arrest by activating ERβ and thereafter inactivating NF-κB or directly inducing expression of cell cycle checkpoints.…”

Genistein induces apoptosis in vitro and has antitumor activity against human leukemia HL‐60 cancer cell xenograft growth in vivo

“…Genistein, a soybean‐derived isoflavonoid compound, has been shown to have health benefits effects on diverse cell functions . Numerous studies have shown that genistein‐induced antitumor activities through antioxidant, anti‐proliferation, the inactivation of MAPK pathway, induction cancer cell apoptosis, anti‐migration, inactivated glucose transporters (GLUT1), and Hexokinase 2 (HK2) to suppress aerobic glycolysis, induced estrogenic activity as an estrogen receptor agonist and down‐regulating thioredoxin‐1 in human hepatocellular carcinoma SNU‐449 cells . Genistein induces caspase‐independent apoptosis through inhibition of the NF‐κB pathway in T‐cell leukemia cells .…”

DNA Methylation as a Therapeutic Target for Bladder Cancer

“…Genistein interacts with the catalytic domain of DNMT1, competing with hemi-methylated DNA for the catalytic pocket [ 120 ]. Furthermore, in colon cancer cells, genistein demethylated WIF1 and decreased invasiveness and migration of cancer cells by reducing expression of matrix metalloproteinases 2 and 9 [ 121 ]. Curcumin, a polyphenol compound with anti-inflammatory properties, also influences methylation status.…”