Unknown

Dataset Information

0

AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition.


ABSTRACT: Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291. The anti-tumor effects of AZD9291 on breast cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected. MicroRNA array assay, luciferase reporter assay, and qRT-PCR were conducted to identify the interaction and regulation among AZD9291, EZH2, and miR-34a. We discovered that, AZD9291, a potent and selective EGFR inhibitor, disrupted the interaction of EZH2-EED, leading to impairment of PRC2 activity and downregulation of EZH2 protein. In addition, AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor, miR-34a. Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.

SUBMITTER: Zhang KL 

PROVIDER: S-EPMC7468275 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition.

Zhang Kai-Li KL   Shen Qian-Qian QQ   Fang Yan-Fen YF   Sun Yi-Ming YM   Ding Jian J   Chen Yi Y  

Acta pharmacologica Sinica 20190606 12


Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP  ...[more]

Similar Datasets

| S-EPMC9388591 | biostudies-literature
| S-EPMC6531619 | biostudies-literature
| S-EPMC9214623 | biostudies-literature
2023-06-02 | GSE228010 | GEO
| S-EPMC3328302 | biostudies-literature
| S-EPMC11293321 | biostudies-literature
| S-EPMC10009975 | biostudies-literature
2022-06-18 | GSE206009 | GEO
| S-EPMC6928308 | biostudies-literature
| S-EPMC4865918 | biostudies-literature