关键词: 胰腺癌, PANC-1, 组蛋白赖氨酸去甲基化酶1, 过氧化物酶增殖体激活受体辅激动子-1&alpha, sirtuins家族去乙酰化酶3, 表观遗传调控

Abstract:

Background and purpose: Lysine specific demethylase 1(LSD1) is an important chromatin modifier. It epigenetically regulates gene expression pattern through chromatin modification and participates in maintenance of tumor malignant properties, such as oncogenesis, development, invasion, migration and metabolic transformation. SIRT3 (sirtuin 3) is a mitochondria localized tumor suppressor and regulates tumor metabolic transformation and oxidative stress. The correlation between LSD1 and SIRT3 has never been reported before. This study aimed to elucidate the correlation between LSD1 and SIRT3 with gene transcriptional regulation methods. Methods: RNA interference technique, co-immunoprecipitation assay(CoIP), chromatin immune-precipitation assay(ChIP) and firefly luciferase activity assay were employed to elucidate the correlation between LSD1 and SIRT3 in pancreatic cancer. Results: mRNA and protein levels of SIRT3 were significantly elevated in LSD1 knock-down PANC-1 cells. LSD1 interacts with PGC-1α, an important regulator of SIRT3 gene expression. LSD1 and PGC-1α occupied the same region in SIRT3 promoter region through ChIP analysis. Luciferase activity assay validated LSD1 as a negative regulator of PGC-1α in SIRT3 gene transcriptional regulation. Conclusion: LSD1, as an important tumor promoter, negatively regulates the expression of tumor suppressor gene SIRT3, these results provide important clues for the role that LSD1 plays in aberrant metabolism and oxidative stress.

Key words: Pancreatic cancer, Lysine specific demethylase 1, Peroxisome proliferator-activated receptor gamma, Coactivator 1 alpha, Sirtuin 3, Epigenetic regulation