Estrogen-induced hypomethylation and overexpression of YAP1 facilitate breast cancer cell growth and survival

Abstract

Increased expression of Yes-associated protein-1 ( YAP1 ) was shown to correlate with reduced survival in breast cancer (BC) patients. However, the exact mechanism of YAP1 regulation in BC cells remains ambiguous. Genomic sequence search showed that the promoter region of the YAP1 gene contains CpG Islands, hence the likelihood of epigenetic regulation by DNA methylation. To address this possibility, the effect of estrogen (17β estradiol; E2) on YAP1 gene expression and YAP1 promoter methylation status was evaluated in BC cells. The functional consequences of E2 treatment in control and YAP1 -silenced BC cells were also investigated. Our data showed that E2 modulates YAP1 expression by hypomethylation of its promoter region via downregulation of DNA methyltransferase 3B (DNMT3B); an effect that seems to facilitate tumor progression in BC cells. Although the effect of E2 on YAP1 expression was estrogen receptor (ER) dependent, E2 treatment also upregulated YAP1 expression in MDA-MB231 and SKBR3 cells, which are known ER-negative BC cell lines but expresses ERα. Functionally, E2 treatment resulted in increased cell proliferation, decreased apoptosis, cell cycle arrest, and autophagic flux in MCF7 cells. The knockdown of the YAP1 gene reversed these carcinogenic effects of E2 and inhibited E2-induced autophagy. Lastly, we showed that YAP1 is highly expressed and hypomethylated in human BC tissues and that increased YAP1 expression correlates negatively with DNMT3B expression but strongly associated with ER expression. Our data provide the basis for considering screening of YAP1 expression and its promoter methylation status in the diagnosis and prognosis of BC.

Activation of GPER by E2 promotes proliferation, invasion and migration of breast cancer cells by regulating the miR‑124/CD151 pathway

“…E2 is involved in the induction of malignant transformation of several types of cancer cells via regulation of the associated biological processes, such as proliferation, invasion and migration ( 14 , 15 ). Most of the biological effects of estrogens are mediated via binding and activation of the classic estrogen receptors (ERs) ( 16 ). The G protein -coupled estrogen receptor (GPER) is also denoted as G protein receptor 30 (GPR30) and has been demonstrated to bind to E2 ( 17 ).…”

Effects of YAP1 and SFRP2 overexpression on the biological behavior of colorectal cancer cells and their molecular mechanisms

“…In the Hippo/YAP1 signaling pathway, the activation of YAP1 is associated with tumor acquisition of malignant characteristics, including anti-cancer therapy resistance, the metastasis of cancer stem cells, and epithelial-mesenchymal transformation (5)(6)(7). In addition, YAP1 has been shown to be associated with poor prognosis and reduced survival in many human cancers (8)(9)(10). Thus, YAP1 can be used as a marker of poor prognosis and drug resistance in cancers.…”

Comprehensive Characterization of m6A Regulators-Mediated Methylation Modification Patterns and Tumor Microenvironment Signature in Breast Cancer

“…The dysregulation of epigenetic modi cations is a common feature of most human cancers, including breast cancer [33,34,35]. Apart from DNA methylation and protein phosphorylation or histone modi cations, RNA m6A modi cation has been identi ed as another important layer of epigenetic modi cation in transcription and translation [36], which are involved in regulating RNA stability, RNA export, protein translation, and stem cell renewal [4,37].…”