Curcumol Controls Choriocarcinoma Stem-Like Cells Self-Renewal via Repression of DNA Methyltransferase (DNMT)- and Histone Deacetylase (HDAC)-Mediated Epigenetic Regulation
Zheng Peng, Wenjun Zhou, Chun Zhang, Huining Liu, Yi Zhang
Department of Gynecology and Obstetrics, Xiangya Hospital of Central South University, Changsha, Hunan, China (mainland)
Med Sci Monit 2018; 24: LBR461-472
Available online: 2018-01-24
Cancer stem cells (CSCs), in choriocarcinoma and other carcinomas, possess the ability of self-renewal and multilineage differentiation potential. We previous isolated choriocarcinoma cancer stem-like cells (CSLCs), which hold the stemness characteristics of CSCs. Epigenetic modifications have emerged as drivers in tumorigenesis, but the mechanisms of CSCs are largely unknown, and new drug therapies are needed to break the persistence of CSCs.
MATERIAL AND METHODS: Quantitative real-time PCR (qRT-PCR) and Western blot analysis were performed to detect the expression of DNMTs, HDACs, and stemness-genes. DNMTs and HDACs silencing and overexpressing lentivirus were transfected into JEG-3 cells to investigate the epigenetic functions in CSLCs. In vivo expression of curcumol effects of CSLCs on DNMTs and HDACs were analyzed by immunohistochemistry.
RESULTS: Expression of DNMT1, DNMT3b, HDAC1, and HDAC3 were increased in choriocarcinoma CSLCs. Consistent with the inhibitory effect of 5-AzaC and TSA on CSLCs, DNMT/HDAC knockdown displayed significant repression of self-renewal in CSLCs. Curcumol inhibited the stemness ability of CSLCs in vitro and in vivo, and the inhibitory effect we observed was mediated in part through repressing activity of DNMTs and HDACs. Importantly, curcumol showed a better effect than DNMT and HDAC inhibitors combined in eliminating CSLCs.
CONCLUSIONS: These findings indicate that DNMT- and HDAC-mediated epigenetic regulation plays an important role in the biology of choriocarcinoma CSLCs, and curcumol has the potential to be a new drug to fight CSLCs, warranting further investigation of epigenetic-based therapies.
Keywords: Choriocarcinoma, DNA Methylation, Histone Deacetylases, Neoplastic Stem Cells