| Summary: | 碩士 === 長庚大學 === 生物醫學研究所 === 99 === Aberrant epigenetic changes in DNA and histone modifications are hallmarks of most cancers, suggesting that these reversible epigenetic modifications play important roles in cancer progression. Lysine specific demethylase 1 (LSD1) was the first identified histone demethylase which participated in many gene suppressor complexes and repressed several tumor suppressor genes. To investigate the role of LSD1 in human malignancies, we analyzed the genome-wide gene expression pattern in 211 pairs of hepatocellular carcinoma (HCC) and adjacent normal tissues using the data deposited in public database (GSE14520) to identify differentially expressed pathways by Gene Set Enrichment Analysis (GSEA). We found that the expression levels of LSD1 were significantly elevated in HCC tissues, and knocked down of LSD1 restored the aberrantly expressed pathways, including cell cycle, DNA replication, amino acid and drug metabolism. To validate the role of LSD1 in HCC tumorigenesis, we knocked down the expression of LSD1 in HCC cells using small interfering RNA (siRNA) technology. SiRNA-mediated silencing of LSD1 significantly suppressed the proliferation and colony formation of cultured HCC cells. Flow cytometry analysis revealed that silencing of LSD1 led to cell cycle arrest at the G0/G1 stage and also suppressed DNA synthesis in HepG2 cells. In addition, LSD1 depletion up-regulated multiple CDK inhibitor genes, such as p15, p21 and p27, and increased the number of senescence positive cells, suggesting that LSD1 may contribute to HCC progression by stimulating cell proliferation and suppressing cellular senescence. These results suggest that LSD1 may play an important role in HCC progression. Inhibition of LSD1 activity could provide a potential therapeutic strategy in cancer treatment.
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