Zinc-finger protein 545 is inactivated due to promoter methylation and functions as a tumor suppressor through the Wnt/β-catenin, PI3K/AKT and MAPK/ERK signaling pathways in colorectal cancer

Abstract

The transcription factor, zinc-finger protein 545 (ZNF545), that belongs to the Kruppel-associated box zinc-finger protein (KRAB-ZFP) family, acts as a tumor suppressor and is inactivated by promoter methylation in cancers such as nasopharyngeal carcinoma, breast cancer, and gastric cancer, but its role in colorectal cancer (CRC) is unknown. The purpose of this study was to characterize the ZNF545 expression, methylation status, biological function, and related molecular mechanisms in CRC. The results showed that ZNF545 was expressed in adult normal colorectal tissues, but downregulated or silenced in CRC cell lines, and this mechanism was reversed by demethylation treatment with 5-aza-2′-deoxycytidine and trichostatin A. The results also showed that the expression of ZNF545 in primary CRC tissues was significantly downregulated compared to adjacent tissues (p<0.05). Overexpression of ZNF545 caused CRC cell cycle arrest and apoptosis, suppressed cell proliferation, and suppressed colony formation and migration in vitro, showing that ZNF545 can function as a tumor suppressor. This function was also shown in nude mice. Furthermore, Wnt/β-catenin, phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways participated in the regulation of ZNF545 in CRC cells. Together, the results suggested that ZNF545 functions as a tumor suppressor in CRC and is frequently inactivated by promoter methylation.

Diosgenin inhibits the epithelial‑mesenchymal transition initiation in osteosarcoma cells via the p38MAPK signaling pathway

“…However, the MAPK signaling pathway is involved in a number of functions associated with cancerous behaviors. In addition to the initiation of EMT, the MAPK signaling pathway additionally serves roles in cell growth, apoptosis and inflammation (58)(59)(60)(61). A previous study has shown that diosgenin can inhibit the cell cycle of osteosarcoma cells through the P38 protein (62).…”

Genome‐wide screening of abberant methylated drivers combined with relative risk loci in bladder cancer

“…In gastric cancer, SPG20 might be suppressed by methylation and result in activation of cell proliferation by upregulated the EGFR/MAPK pathway . Xiang et al demonstrated that zinc‐finger protein 545 is silenced by promoter methylation and acted as an inhibiting factor in colorectal cancer through the Wnt/β‐catenin, PI3K/AKT and MAPK/ERK signaling pathways . In colorectal cancer, it was also found that aberrant DNA methylation of WNT pathway genes might regulate tumor progression .…”

The expression signature of cancer‐associated KRAB‐ZNF factors identified in TCGA pan‐cancer transcriptomic data

“…A growing number of reports indicate that certain members of the KRAB‐ZNF family are involved in various aspects of carcinogenesis. For example, ZNF545 negatively controls cellular proliferation, and its expression is reduced in multiple malignancies due to promoter hypermethylation (Xiang et al ., ; Xiao et al ., ). A tumor suppressor role was also described for ZBRK1 (Chen et al ., ; Lin et al ., ) and ZNF307 (Liang et al ., ).…”