Resveratrol inhibits the proliferation of estrogen receptor-positive breast cancer cells by suppressing EZH2 through the modulation of ERK1/2 signaling
- 251 Downloads
Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in breast cancer and plays an important role in maintaining the cell proliferative capacity. However, the mechanisms underlying the transcriptional regulation of EZH2 in estrogen receptor (ER)-positive breast cancer cells remain unclear. The antitumor effects of resveratrol have been reported. However, whether EZH2 was involved in these effects needs further exploration. Here, we showed that EZH2 is required for estrogen-induced cell proliferation in ER-positive breast cancer. Exposure to 17β-estradiol (E2) upregulated EZH2 via ERα signaling, and this effect was blocked by U0126, a MEK inhibiter. Resveratrol inhibited the proliferation and colony formation in ER-positive breast cancer cells and downregulated EZH2 through inhibition of phospho-ERK1/2. These findings indicated that ERK1/2 and ER signaling–mediated EZH2 upregulation is crucial for the proliferation of ER-positive breast cancer cells. The suppression of EZH2 expression by ERK1/2 dephosphorylation is important for the antiproliferative activities of resveratrol against ER-positive breast cancer cells.
KeywordsEZH2 Estrogen receptor Phospho-ERK1/2 Resveratrol Proliferation
This work was supported by the National Natural Science Foundation of China [grant numbers 81573183, 81673205]; the Major Program of Natural Science Research of Jiangsu Higher Education Institutions [grant number 15KJA330001]; the Center for Global Health, School of Public Health, Nanjing Medical University; and the project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006;24:268–73.CrossRefGoogle Scholar
- Bhat KPL, Pezzuto JM. Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells. Cancer Res. 2001;61:6137–44.Google Scholar
- Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res. 2001;61:7456–63.Google Scholar
- Caristi S, Galera JL, Matarese F, Imai M, Caporali S, Cancemi M, et al. Estrogens do not modify MAP kinase-dependent nuclear signaling during stimulation of early G (1) progression in human breast cancer cells. Cancer Res. 2001;61:6360–6.Google Scholar
- Chung SS, Dutta P, Austin D, Wang P, Awad A, Vadgama JV. Combination of resveratrol and 5-flurouracil enhanced anti-telomerase activity and apoptosis by inhibiting STAT3 and Akt signaling pathways in human colorectal cancer cells. Oncotarget. 2018;9:32943–57.Google Scholar
- Kiskova T, Demeckova V, Jendzelovska Z, Kiktava M, Venglovska K, Bohmdorfer M, et al. Nocturnal resveratrol administration inhibits chemically induced breast cancer formation in rats. J Physiol Pharmacol. 2017;68:867–75.Google Scholar
- Li D, Wang G, Jin G, Yao K, Zhao Z, Bie L, et al. Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway. Int J Mol Med. 2019;43:630–40.Google Scholar
- Liu H, Du J, Hu C, Qi H, Wang X, Wang S, et al. Delayed activation of extracellular-signal-regulated kinase 1/2 is involved in genistein- and equol-induced cell proliferation and estrogen-receptor-alpha-mediated transcription in MCF-7 breast cancer cells. J Nutr Biochem. 2010;21:390–6.CrossRefGoogle Scholar
- Zangooei M, Nourbakhsh M, Ghahremani MH, Meshkani R, Khedri A, Shadboorestan A, et al. Investigating the effect of visfatin on ERalpha phosphorylation (Ser118 and Ser167) and ERE-dependent transcriptional activity. EXCLI J. 2018;17:516–25.Google Scholar