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...

Polychlorinated biphenyl (PCB) quinones are known to cause toxic effects, but their mechanisms are quite unclear. In this study, we examined whether 2,3,5-trichloro-6-phenyl-[1,4]benzoquinone, PCB29-pQ, induces cell death via apoptosis pathway. Our result showed PCB29-pQ exposure decreased HepG2 cell viability in a time-dependent manner. Lactate dehydrogenase leakage assay also implied the cytotoxicity of PCB29-pQ. 4',6-Diamidino-2-phenylindole dihydrochloride staining and flow cytometry assays both confirmed PCB29-pQ caused dose-dependent apoptotic cell death in HepG2 cells. Furthermore, we found that PCB29-pQ exposure increased cellular reactive oxygen species (ROS) level, decreased mitochondrial membrane potential and induced the translocation of cytochrome c from mitochondria into cytosol in HepG2 cells. Moreover, PCB29-pQ exposure induced B-cell lymphoma 2 (Bcl-2) downregulation and Bcl-2-associated X (Bax) upregulation, poly(ADP-ribose) polymerase cleavage, accompanied with the increased caspase-3/9 and p53 expressions. Taking together, these results suggested PCB29-pQ induced HepG2 cells apoptosis through a ROS-driven, mitochondrial-mediated and caspase-dependent pathway.

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Pancreatic cancer is a serious solid malignant tumor worldwide. Increasing evidence has pointed out that abnormal expressions of long noncoding RNAs are involved in various tumors. Meanwhile, LINC00052 is reported as a famous tumor regulator in several cancers. Nevertheless, the biological role of LINC00052 in pancreatic cancer progression is still unknown. Our study was to explore the specific mechanism of LINC00052 in pancreatic cancer. First, we observed that the LINC00052 was obviously downregulated in several pancreatic cancer cell lines. Overexpression of LINC00052 greatly repressed AsPC‐1 and SW1990 cell proliferation, triggered the apoptosis and prevented cell cycle in the G1 phase. For another, AsPC‐1 and SW1990 cell migration and invasion capacity were also obviously repressed by LINC00052 upregulation. Moreover, miR‐330‐3p was elevated in pancreatic cancer cells and can function as a target of LINC00052 confirmed by luciferase reporter and RNA Immunoprecipitation (RIP) experiments. Inhibition of miR‐330‐3p could depress pancreatic cancer progression while overexpressed miR‐330‐3p exhibited an opposite process. Finally, our data indicated that the LINC00052 also remarkably suppressed pancreatic tumor growth via modulating miR‐330‐3p in vivo. To conclude, our study revealed that the LINC00052 might provide a new perspective for pancreatic cancer therapy.

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