Abstract 603: Targeted Casp8AP2 methylation increased drug resistance in mesenchymal stem cell and cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.603-603
• Main Authors: Leu, Yu-Wei, Pai, Mei-Yu, Hsu, Chia-Chen, Lee, Kuan-Der, Chen, Chih-Cheng, Chen, Yao-Li, Huang, Tim H.-M., Hsiao, Shu-Huei
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-603

Casp8AP2 is a FLASH protein that is critical for the formation of death complex and the relay of death signal into the cells. Genetic defect of Casp8AP2 was found in diseases like acute lymphoblastic leukemia, implying that the miss-expression of Casp8AP2 might cause disease. On the other hand, the promoter of Casp8AP2 is enriched with CpG islands and we observed differential methylation changes within Casp8AP2 promoter during mesenchymal stem cell (MSCs) differentiation. Aberrant DNA methylation was also identified within the Casp8AP2 promoter in vivo like in liver cancers. It was then hypothesized that the abnormal DNA methylation within the Casp8AP2 promoter might contribute to the enhanced survival or drug resistance in cancer development. We determined the epigenetic states within the Casp8AP2 promoter in different cells and confirmed that there are methylation differences between the normal and tumoral samples within the Casp8AP2 promoter. Differential methylation was also observed between the drug resistant cancer cells and primary cancer cells. Global demethylation in drug resistant cell lines reversed the Casp8AP2 methylation, which was correlated with the reversed resistance phenotype. We then target-methylated the Casp8AP2 promoter in normal somatic stem cells and cancer cells like MDA-MB-231 and found increased drug resistance in these cells. These data point out that methylation within the death complex like Casp8AP2 might be able to serve as biomarker and treatment target for drug resistance in cancer cells. (Supported in part by NSC100-2320-B-194-001) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 603. doi:1538-7445.AM2012-603