Resveratrol Exhibits Diverse Anti-cancer Activities Through Epigenetic Regulation of E-cadherin and P21 in Triple-negative Breast Cancer Cells

Overview

Journal Breast Cancer

Specialty Oncology

Date 2023 May 11

PMID 37166625

Authors

Takako Sakamoto

Keiji Tanimoto

Hidetaka Eguchi

Shunta Sasaki

Kouki Tsuboi

Shin-Ichi Hayashi

Sahoko Ichihara

Affiliations

Soon will be listed here.

Abstract

Background: Triple-negative breast cancer (TNBC) has an aggressive phenotype and poor outcome, however no specific targeted therapy has been established for TNBC lacking germline BRCA1/2 pathogenic variants. To develop a novel therapeutic strategy, we explored the potential of resveratrol (RSV) for TNBC treatment.

Methods: We investigated the effects of RSV on malignant phenotypes of TNBC cells as well as on apoptosis induced by ABT263, a specific inhibitor of BCL-2 and BCL-xL, using morphological observation, migration assay, β-galactosidase staining, and Hoechst staining. To elucidate the underlying mechanisms of RSV-mediated effects, expression levels and histone acetylation levels of cadherin 1 (CDH1, E-cadherin) and cyclin dependent kinase inhibitor 1A (CDKN1A, p21) were determined by RT-qPCR, western blotting, and chromatin immunoprecipitation. Furthermore, knockdown analysis was conducted to evaluate the involvement of E-cadherin and/or p21 in RSV potentiation on cytotoxic activity of ABT263.

Results: RSV treatment induced epithelial-like cellular morphology and suppressed the migration capacity in MDA-MB-231 and BT-549-Luc TNBC cells. β-galactosidase-positive cells were increased after RSV treatment, indicating the induction of cellular senescence, in MDA-MB-231 cells but not in BT-549-Luc cells. RSV increased the expression and histone acetylation of CDH1 and CDKN1A in both cells. Interestingly, pre-treatment with RSV enhanced the induction of apoptosis in the ABT263-treated MDA-MB-231 and BT-549-Luc cells, and knockdown of CDKN1A decreased ABT263-induced apoptosis in RSV-treated MDA-MB-231 cells.

Conclusions: RSV represses the metastatic capacity and enhances the cytotoxic activity of ABT263 in TNBC cells. Our results suggested that RSV can potentially be used as a repressor of metastasis or a sensitizer to ABT263 for TNBC treatment via up-regulation of CDH1 and CDKN1A through epigenetic mechanisms.

References

Waks A, Winer E . Breast Cancer Treatment: A Review. JAMA. 2019; 321(3):288-300. DOI: 10.1001/jama.2018.19323. View

Turk A, Wisinski K . PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside. Cancer. 2018; 124(12):2498-2506. PMC: 5990439. DOI: 10.1002/cncr.31307. View

Garrido-Castro A, Lin N, Polyak K . Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 2019; 9(2):176-198. PMC: 6387871. DOI: 10.1158/2159-8290.CD-18-1177. View

Liu J, Sun X, Qin S, Wang H, Du N, Li Y . CDH1 promoter methylation correlates with decreased gene expression and poor prognosis in patients with breast cancer. Oncol Lett. 2016; 11(4):2635-2643. PMC: 4812319. DOI: 10.3892/ol.2016.4274. View

Shen T, Zhang K, Siegal G, Wei S . Prognostic Value of E-Cadherin and β-Catenin in Triple-Negative Breast Cancer. Am J Clin Pathol. 2016; 146(5):603-610. DOI: 10.1093/ajcp/aqw183. View

Kourtidis A, Lu R, Pence L, Anastasiadis P . A central role for cadherin signaling in cancer. Exp Cell Res. 2017; 358(1):78-85. PMC: 5544584. DOI: 10.1016/j.yexcr.2017.04.006. View

Singh A, Settleman J . EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010; 29(34):4741-51. PMC: 3176718. DOI: 10.1038/onc.2010.215. View

Somlo G, Chu P, Frankel P, Ye W, Groshen S, Doroshow J . Molecular profiling including epidermal growth factor receptor and p21 expression in high-risk breast cancer patients as indicators of outcome. Ann Oncol. 2008; 19(11):1853-9. PMC: 2733077. DOI: 10.1093/annonc/mdn402. View

Zohny S, Al-Malki A, Zamzami M, Choudhry H . p21: its paradoxical effect in the regulation of breast cancer. Breast Cancer. 2018; 26(2):131-137. DOI: 10.1007/s12282-018-0913-1. View

10.

Georgakilas A, Martin O, Bonner W . p21: A Two-Faced Genome Guardian. Trends Mol Med. 2017; 23(4):310-319. DOI: 10.1016/j.molmed.2017.02.001. View

11.

Singh A, Bishayee A, Pandey A . Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy. Nutrients. 2018; 10(6). PMC: 6024317. DOI: 10.3390/nu10060731. View

12.

Ediriweera M, Tennekoon K, Samarakoon S . Emerging role of histone deacetylase inhibitors as anti-breast-cancer agents. Drug Discov Today. 2019; 24(3):685-702. DOI: 10.1016/j.drudis.2019.02.003. View

13.

Tate C, Rhodes L, Segar H, Driver J, Pounder F, Burow M . Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat. Breast Cancer Res. 2012; 14(3):R79. PMC: 3446342. DOI: 10.1186/bcr3192. View

14.

Shah P, Gau Y, Sabnis G . Histone deacetylase inhibitor entinostat reverses epithelial to mesenchymal transition of breast cancer cells by reversing the repression of E-cadherin. Breast Cancer Res Treat. 2013; 143(1):99-111. DOI: 10.1007/s10549-013-2784-7. View

15.

Carlos-Reyes A, Lopez-Gonzalez J, Meneses-Flores M, Gallardo-Rincon D, Ruiz-Garcia E, Marchat L . Dietary Compounds as Epigenetic Modulating Agents in Cancer. Front Genet. 2019; 10:79. PMC: 6406035. DOI: 10.3389/fgene.2019.00079. View

16.

Chatterjee B, Ghosh K, Kanade S . Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21 in human breast cancer cell lines. Biofactors. 2019; 45(5):818-829. DOI: 10.1002/biof.1544. View

17.

Sinha D, Sarkar N, Biswas J, Bishayee A . Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms. Semin Cancer Biol. 2016; 40-41:209-232. DOI: 10.1016/j.semcancer.2015.11.001. View

18.

Sakamoto T, Horiguchi H, Oguma E, Kayama F . Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J Nutr Biochem. 2009; 21(9):856-64. DOI: 10.1016/j.jnutbio.2009.06.010. View

19.

Ji S, Zheng Z, Liu S, Ren G, Gao J, Zhang Y . Resveratrol promotes oxidative stress to drive DLC1 mediated cellular senescence in cancer cells. Exp Cell Res. 2018; 370(2):292-302. DOI: 10.1016/j.yexcr.2018.06.031. View

20.

Li H, Huang J, Yang B, Xiang T, Yin X, Peng W . Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β-catenin signaling pathway. Toxicol Appl Pharmacol. 2013; 272(1):180-90. DOI: 10.1016/j.taap.2013.05.011. View