Histone demethylase JMJD1A promotes colorectal cancer growth and metastasis by enhancing Wnt/β-catenin signaling

Abstract

The abbreviations used are: JMJD1A, jumonji domain containing 1A; CRC, colorectal cancer; PCNA, proliferating cell nuclear antigen; MMP9, matrix metallopeptidase 9; IP, immunoprecipitation; ChIP, chromatin immunoprecipitation; H3K9, histone-3 lysine-9; GEO, Gene Expression Omnibus. Key words: histone demethylase; JMJD1A; epigenetics; colorectal cancer; proliferation; metastasis; Wnt/β-catenin signaling ABSTRACTThe histone demethylase Jumonji domain containing 1A (JMJD1A) is overexpressed in multiple tumors and promotes cancer progression. JMJD1A has been shown to promote colorectal cancer (CRC) progression, but its molecular role in CRC is unclear. Here, we report that JMJD1A is overexpressed in CRC specimens and that its expression is positively correlated with that of proliferating cell nuclear antigen (PCNA). JMJD1A knockdown decreased the expression of proliferative genes such as c-Myc, cyclin D1, and PCNA, suppressed CRC cell proliferation, arrested cell cycle progression, and reduced xenograft tumorigenesis. Furthermore, JMJD1A knockdown inhibited CRC cell migration, invasion, and lung metastasis by decreasing matrix metallopeptidase 9 (MMP9) expression and enzymatic activity. Moreover, bioinformatics analysis of GEO profile datasets revealed that JMJD1A expression in human CRC specimens is positively correlated with the expression of Wnt/β-catenin target genes, including c-Myc, cyclin D1, and MMP9. Mechanistically, JMJD1A enhanced Wnt/β-catenin signaling by promoting β-catenin expression and interacting with β-catenin to enhance its transactivation. JMJD1A removed the methyl groups of the H3K9me2 at the promoters of c-Myc and MMP9 genes. In contrast, the JMJD1A H1120Y variant, which lacked demethylase activity, did not demethylate H3K9me2 at these promoters, failed to assist β-catenin to induce the expression of Wnt/β-catenin target genes, and failed to promote CRC progression. These findings suggest that JMJD1A's demethylase activity is required for Wnt/β-catenin activation. Of note, high JMJD1A levels in CRC specimens predicted poor cancer outcomes. In summary, JMJD1A promotes CRC progression by enhancing Wnt/β-catenin signaling, implicating JMJD1A as a potential molecular target for CRC management.Colorectal cancer (CRC) is the third most commonly diagnosed cancers in males and the second in females, with an established 1.4 million new cases and 693,900 deaths occurring in the worldwide in 2012(1). In China, colorectal cancer is the fifth most commonly diagnosed cancers in males and the forth in females, and is the fifth leading causes of cancer death in 2015(2). The high incidence and mortality of CRC urge us to figure out the molecular mechanism of CRC progression and develop effective therapeutics. However, the potential mechanism which triggers CRC development is not clearly identified.Aberrant activation of Wnt/β-catenin signaling pathway, mostly caused by the mutations of the tumor suppressor APC or oncogene β-catenin, is found in 90% of human CRC specimens and plays an essential role in CRC prog...

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