PDF(Pubmed)
Abstract：
Epigenetic changes are common in cancer and include aberrant DNA methylation and histone modifications, including both acetylation or methylation. DNA methylation in the promoter regions and histone deacetylation are usually accompanied by gene silencing, and may lead to the suppression of tumor suppressors in cancer cells. An interaction between epigenetic pathways has been reported that could be exploited to more efficiently target aggressive cancer cells, particularly those against which current treatments usually fail, such as pancreatic cancer. In this study, we explored the possibility to combine the DNA demethylating agent 5-AZA with HDAC inhibitor SAHA to treat pancreatic cancer cell lines, focusing on the acetylation of mutp53 and the consequences on its stability, as well as on the interaction of this protein with c-myc and BRCA-1, key molecules in cancer survival. The results obtained suggest that SAHA/5-AZA combination was more effective than single treatments to promote the degradation of mutp53, to upregulate p21 and downregulate c-Myc and BRCA-1, thus increasing DNA damage and cytotoxicity in pancreatic cancer cells.
摘要：
表观遗传变化在癌症中很常见，包括异常的DNA甲基化和组蛋白修饰。包括乙酰化或甲基化。启动子区域的DNA甲基化和组蛋白脱乙酰通常伴随着基因沉默，并可能导致癌细胞中肿瘤抑制因子的抑制。据报道，表观遗传途径之间的相互作用可用于更有效地靶向侵袭性癌细胞。特别是那些目前的治疗通常失败，比如胰腺癌。在这项研究中,我们探索了将DNA去甲基化剂5-AZA与HDAC抑制剂SAHA联合治疗胰腺癌细胞系的可能性，专注于mutp53的乙酰化及其稳定性的后果，以及该蛋白与c-myc和BRCA-1的相互作用，这些是癌症生存的关键分子。获得的结果表明，SAHA/5-AZA组合比单一治疗更有效地促进mutp53的降解，上调p21并下调c-Myc和BRCA-1，从而增加胰腺癌细胞的DNA损伤和细胞毒性。
