J Pharm Pharmacogn Res 3(suppl. 1): S66, 2015
Proceedings of the 4th International Symposium on Pharmacology of Natural Products FAPRONATURA 2015 September 21st-25th, 2015; Cuban Society of Pharmacology. Topes de Collantes, Sancti Spiritus, Cuba.
OC-48: WITHAFERIN A INDUCED DNA HYPERMETHYLATION CONTRIBUTES TO SILENCING OF TUMOR PROMOTING GENES IN TRIPLE NEGATIVE BREAST CANCER
Szarc vel Szic K1, Declerck K1, Crans RAJ1, Diddens J1, Scherf D2, Gerhäuser C2, Vanden Berghe W1.
Withaferin A (WA), isolated from the plant Withania somnifera (Indian name, Ashwagandha), is a steroidal lactone, which holds promise as a chemopreventive agent for treatment of triple negative breast cancer. By Infinium HumanMethylation450, we determined genome-wide DNA methylation profiles in non-metastatic MCF-7 and highly metastatic MDA-MB-231 breast cancer cells, left untreated or exposed for 72h to pharmacologically effective concentrations of WA. Remarkably, in contrast to DNA hypomethylation effects triggered by global cancer epigenetic drugs (i.e. 5-aza-2’-deoxycytidine), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific hypermethylation of multiple tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), as well as genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Furthermore, promoter-specific loss of active H3K4me3 chromatin mark and DNA hypermethylation in response to WA silences PLAU gene expression and suppresses invasive tumor behavior. Overall, our data suggest that WA treatment of triple negative breast cancer cells suppresses multiple cancer hallmarks and silences invasion-related gene expression through epigenetic reprogramming, involving interplay of JARID1B (KDM5B) induced loss of histone K4 tri-methylation and DNA hypermethylation.
Citation Format: Szarc vel Szic K, Declerck K, Crans RAJ, Diddens J, Scherf D, Gerhäuser C, Vanden Berghe W (2015) Withaferin A induced DNA hypermethylation contributes to silencing of tumor promoting genes in triple negative breast cancer. [Abstract]. In: Proceedings of the FAPRONATURA 2015; 2015 Sep 21-25; Topes de Collantes, Sancti Spiritus: CSF. J Pharm Pharmacogn Res 3(Suppl. 1): S66. Abstract nr OC-48.