LUCAT1 Epigenetically Downregulates the Tumor Suppressor Genes CXXC4 and SFRP2 in Gastric Cancer

Abstract

Purpose The mechanisms of Wnt/β-catenin pathway signaling and abnormal expression of tumor suppressor genes is not well known in gastric cancer (GC). Long non-coding RNA (lncRNA) has recently been identified as a possible link therein. In this study, we investigated the role of lung cancer associated transcript 1 (LUCAT1) in GC. Materials and Methods The expression of LUCAT1 in GC cell lines and 100 tissue samples was examined by qRT-PCR. Two different siRNAs were used for knockdown of LUCAT1 expression. Cell viability was assessed by MTT assay. To analyze metastasis, scratch wound-healing assay, a Matrigel invasion assay, and colony formation assay were performed. Apoptosis was analyzed by PI/Annexin-V staining. To check the methylation status in tumor suppressor genes, methylation-specific PCR was carried out. Western blot was performed to detect epithelial-mesenchymal transition and apoptosis markers upon silencing of LUCAT1 (siLUCAT1). Results LUCAT1 expression in GC cell lines and tissues was significantly elevated, compared to that in normal gastric cells and adjacent non-tumor tissues ( p <0.001). Two different siRNAs for LUCAT1 reduced cell proliferation, invasion, and migration, compared to siCT ( p <0.05), and these reductions were restored by pcDNA-LUCAT1 ( p <0.05). siLUCAT1 elicited upregulation of the expression of CXXC4 and SFRP2 . The expression of H3K27me3 was reduced by siLUCAT1, and this reduction was correlated with methylation of CXXC4 and SFRP2 . Inhibition of LUCAT1 up-regulated EZH2 expression and resulted in demethylation of CXXC4 and SFRP2 through the Wnt/β-catenin signaling pathway. Conclusion We concluded that LUCAT1 induces methylation of CXXC4 and SFRP2 , thereby regulating Wnt/β-catenin signaling in GC.

Anticancer effects of melatonin via regulating lncRNA JPX‐Wnt/β‐catenin signalling pathway in human osteosarcoma cells

“…74,75 However, the role of lncRNA JPX in OS has not been reported. In this study, the results showed that melatonin inhibited the expression of The Wnt/β-catenin pathway could regulate multi-tumour development, like lung cancer, 76 intestinal tumour, 77 gastric cancer 78 and glioma. 79 Evidence has proved that Wnt/β-catenin pathway…”

“…The Wnt/β‐catenin pathway could regulate multi‐tumour development, like lung cancer, 76 intestinal tumour, 77 gastric cancer 78 and glioma. 79 Evidence has proved that Wnt/β‐catenin pathway could regulate OS cell behaviours.…”

Cancer-derived exosomal circ_0038138 enhances glycolysis, growth, and metastasis of gastric adenocarcinoma via the miR-198/EZH2 axis

“…Consistently, previous literature has identified CXXC4 as a target of EZH2 and that EZH2 can trigger the activation of the Wnt pathway by downregulating CXXC4, thus accelerating the growth of GC cells [27] . CXXC4 has been validated to express poorly in clinical samples of GC patients and act as a tumor suppressor in GC [ 49 , 50 ]. Strikingly, CXXC4 can disrupt the Wnt/β-catenin pathway activation in breast cancer cells by regulating the phosphorylation of GSK-3β, thus affecting the integrity of the β-catenin degradation complex [51] .…”

Regulatory function of DNA methylation mediated lncRNAs in gastric cancer

“…Similarly, it was investigated the functions and molecular mechanisms of LUCAT1 in the carcinogenesis of GC. It was found that LUCAT1 induces methylation of CXXC4 (CXXC finger protein 4), a negative regulator of Wnt/β-catenin signaling and SFRP2, thereby regulating Wnt/β-catenin signaling whose alteration is closely related to the development and progression of GC [ 21 ]. HOTTIP lncRNA, a component of the HomeoboxA cluster in its 5'-end, manipulated multiple processes of cancer like facilitating the proliferation of pancreatic cancer cells [ 101 ], and metastasis of hepatoma [ 102 ].…”

“…Obviously, when it comes to gene regulation, tumor occurrence is an inevitable issue that genome-associated studies have showed a huge number of lncRNAs related to diverse types of cancer [ 20 ]. In addition to the abnormal variant in the course of the tumorous initiation and progression, a growing number of researches will be flocked to lncRNAs exceptionally [ 21 , 22 ]. In a word, lncRNA can not only affect gene expression itself but also regulate gene expression and various signaling pathways by interacting with DNA methylation among a lot of cancers, including gastric cancer [ 23 ].…”