Dataset Information

EZH2 Exacerbates Breast Cancer by Methylating and Activating STAT3 Directly.

ABSTRACT: Breast cancer is one of the most common causes of female death globally. Numerous clinical drugs for breast cancer have been developed, but the unsatisfactory, inevitable side effects and drug resistance are the emerging threatens. Therefore, it is necessary to investigate the comprehensive mechanism of breast cancer. Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver in diverse cancers, such as breast cancer. The canonical role of EZH2 has been vastly investigated, but the non-canonical function of EZH2 in breast cancer remains unclear. Here, we demonstrated that EZH2 exacerbated breast cancer in non-canonical manner by methylating STAT3. EZH2 over-expressed in breast cancer patients and regulated STAT3 post-transcriptionally according to TCGA datasets. Chemical and genetic inhibition of EZH2 impeded proliferation and migration of breast cancer cells, which may be partially rescued by STAT3 over-expression. EZH2 physically interacted with STAT3 and methylated STAT3 directly, resulting in increased nuclear localization and chromatin of STAT3. Furthermore, the mutation of STAT3 methylation site, targeted by EZH2, impeded the transcriptional activity of STAT3. Eventually, disturbed STAT3 methylation by EZH2 in animal model showed decreased breast cancer growth. These data confirm that EZH2 exacerbates breast cancer by methylating STAT3 directly, and thus providing a promising therapeutic target for breast cancer.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC8317538 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundNot all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemotherapy-elicited exosomes in regulating chemoresistance is poorly understood.MethodsUsing commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs.ResultsHere, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome-induced drug resistance in a nude mouse tumor xenograft model.ConclusionThis study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of the WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.

Dataset Information

EZH2 Exacerbates Breast Cancer by Methylating and Activating STAT3 Directly.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets