JMJD2C promotes colorectal cancer metastasis via regulating histone methylation of MALAT1 promoter and enhancing β-catenin signaling pathway

Abstract

BackgroundOur previous work demonstrated that lncRNA-MALAT1 was overexpressed in recurrent colorectal cancer (CRC) and metastatic sites in post-surgical patients. However, the upstream regulatory mechanism of MALAT1 is not well-defined. Histone demethylase JMJD2C holds great potential of epigenetic regulating mechanism in tumor diseases, especially the moderating effect on the promoter activity of targeted genes associated closely with tumor development. Therefore, we herein investigated whether JMJD2C could epigeneticly regulate the promoter activity of MALAT1 and the downstream β-catenin signaling pathway, thereby affecting the metastatic abilities of CRC cells.MethodsJMJD2C expressions in human CRC samples were detected by real-time PCR and immunohistochemistry staining. Gene silencing and overexpressing efficiencies of JMJD2C were confirmed by real-time PCR and western blot. The migration of CRC cells in vitro were tested by transwell and wound healing assays. The protein expression and cellular localization of JMJD2C and β-catenin were characterized by immunofluorescence staining and western blot. The histone methylation level of MALAT1 promoter region (H3K9me3 and H3K36me3) was tested by ChIP-PCR assays. The promoter activity of MALAT1 was detected by luciferase reporter assay. The expressions of MALAT1 and the downstream β-catenin signaling pathway related genes in CRC cells were detected by real-time PCR and western blot, respectively. The nude mice tail vein metastasis model was established to observe the effect of JMJD2C on the lung metastasis of CRC cells in vivo.ResultsOur present results indicated that histone demethylase JMJD2C was overexpressed in matched CRC tumor tissues of primary and metastatic foci, and CRC patients with lower JMJD2C expression in primary tumors had better prognosis with longer OS (Overall Survival). The following biological function observation suggested that JMJD2C promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that JMJD2C protein translocated into the nuclear, lowered the histone methylation level of MALAT1 promoter in the sites of H3K9me3 and H3K36me3, up-regulated the expression of MALAT1, and enhanced the β-catenin signaling pathway in CRC cells.ConclusionOur data demonstrated that JMJD2C could enhance the metastatic abilities of CRC cells in vitro and in vivo by regulating the histone methylation level of MALAT1 promoter, thereby up-regulating the expression of MALAT1 and enhancing the activity of β-catenin signaling pathway, providing that JMJD2C might be a novel therapeutic target for CRC metastasis.

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

“…To date, numerous studies have demonstrated a crucial role for both hypermethylation of tumor suppressor genes and hypomethylation of oncogenes in cancer development and progression [30]. For example, Wu et al [32] found that JMJD2C could enhance the metastasis of colorectal cancer by decreasing the histone methylation of the MALAT1 promoter, thereby upregulating MALAT1 expression and enhancing the activity of the β-catenin signaling pathway. Furthermore, Liang et al [33] identified many novel methylation-regulated differentially expressed genes involved in colon cancer tumorigenesis and progression by identifying hypermethylated downregulated genes and hypomethylated upregulated genes.…”

microRNA-216b enhances cisplatin-induced apoptosis in osteosarcoma MG63 and SaOS-2 cells by binding to JMJD2C and regulating the HIF1α/HES1 signaling axis

“…Histone demethylase jumonji C domain-containing 2C (JMJD2C) is known to demonstrate regulatory potentials in the epigenetic mechanism in malignant diseases, particularly in regard to moderating the influence on the promoter activity of target genes which are strongly associated with tumor development [16]. Prior evidence has proposed that JMJD2C is highly-expressed in OS, and even confers a regulatory role in the context of OS [17].…”

The Emerging Landscape of Long Non-Coding RNAs in Colorectal Cancer Metastasis

“…LncRNA SLCO4A1-AS1 inhibits the interaction of b-catenin with GSKb, inhibits b-catenin phosphorylation, and improves b-catenin stability, ultimately promoting the proliferation, migration, and invasion of CRC cells (82). Wu et al (83) showed that lncRNA JMJD2C promotes CRC metastasis by enhancing the b-catenin signaling pathway and participating in the regulation of histone methylation at the MALAT1 promoter. In addition to directly participating in b-catenin signaling pathway transduction, lncRNAs can also play indirect regulatory roles in this signaling pathway.…”