Abstract
The 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 H3K9me2 at the promoters of c-Myc and MMP9 genes. In contrast, the JMJD1AH1120Y 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.
Highlights
The histone demethylase Jumonji domain containing 1A (JMJD1A) is overexpressed in multiple tumors and promotes cancer progression
We clearly verified a key role of JMJD1A in promoting colorectal cancer (CRC) progression as follows: 1) JMJD1A was frequently overexpressed in human CRC specimens, and knockdatabase. ***, p Ͻ 0.001
Because c-Myc, cyclin D1, and matrix metallopeptidase 9 (MMP9) are target genes of Wnt/-catenin signaling, which is frequently activated in CRC, we were prompted to determine whether JMJD1A promotes CRC progression by enhancement of Wnt/-catenin signaling
Summary
JMJD1A is frequently overexpressed in human CRC specimens and positively correlated with PCNA. Because JMJD1A can cooperate with -catenin to enhance Wnt/-catenin signaling, it was expected that knockdown of JMJD1A reduced the promoter activities of c-Myc, MMP9, and Topflash in HCT116 cells in the absence or presence of LiCl (Fig. 6A). The protein and mRNA levels of c-Myc, cyclin D1, and PCNA were much lower in colon tumors from JMJD1A-deficient mice than from WT mice (Fig. 8, C and D) These results provide the genetic evidence to show that JMJD1A promotes CRC progression by enhancing Wnt/-catenin signaling. The expression of JMJD1A was much higher in CRC specimens than the surrounding nontumorous specimens (Fig. 9A) and positively correlated with PCNA (Fig. 9B), c-Myc (Fig. 9C), cyclin D1 (Fig. 9D), and MMP9 (Fig. 9E), supporting the findings that JMJD1A promotes human CRC progression by enhancing Wnt/catenin signaling. TCGA data showed that the prognosis of CRC patients who have higher levels of JMJD1A in tumors was poorer than the CRC patients with lower levels of JMJD1A in tumors (Fig. 9F)
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