Genome‐wide gain‐of‐function screening identifies EZH2 mediating resistance to PI3Kα inhibitors in oesophageal squamous cell carcinoma

Clinical and Translational Medicine

卷:12

Chunhao Yang¹  Yuxiang Wang²  Linghua Meng²  Mengshi Gao²  Xiang Wang²  Xu Zhang²  Jiajie Shi²  Hui Xing²  Xueling Liu²  Qingyang Ma³  Xiangyin Kong³  Jian Ding⁴ 

[1] Department of Medicinal Chemistry, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China;

[2] Division of Anti‐tumor Pharmacology, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China;

[3] Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health Chinese Academy of Sciences Shanghai China;

[4] School of Pharmaceutical Sciences University of Chinese Academy of Sciences Beijing China;

关键词: CDKN1A;    cell cycle;    CRISPR‐SAM;    CYH33;    ESCC;    EZH2;   

DOI  :  10.1002/ctm2.835

来源: DOAJ

【 摘 要 】

Abstract Phosphoinositide‐3 kinase alpha (PI3Kα) has been confirmed to be a potential therapeutic target for esophageal squamous cell carcinoma (ESCC), while the potency of PI3Kα inhibitors is often attenuated by concurrent oncogenic signalling pathways. We performed genome‐wide gain‐of‐function screening with a CRISPR‐SAM library and identified enhancer of zeste homolog 2 (EZH2) rendering ESCC cells resistant to the PI3Kα inhibitor CYH33. Enhanced expression of EZH2 frequently occurs in ESCC and is related to poor prognosis. Overexpression of full‐length EZH2 but not methyltransferase‐deficient EZH2 conferred resistance to CYH33, while downregulating EZH2 expression restored sensitivity. EZH2 expression was negatively related to the activity of CYH33 against the proliferation of ESCC cell lines and patient‐derived cells. Transcriptomic analysis revealed that EZH2 abrogated CYH33‐mediated cell cycle regulation. EZH2 epigenetically suppressed the transcription of CDKN1A, promoting RB phosphorylation and cell cycle progression. Concurrently targeting EZH2 significantly potentiated CYH33 to inhibit the growth of ESCC cells and patient‐derived xenografts accompanied by enhanced cell cycle arrest. Taken together, our study demonstrated that an EZH2‐p21‐RB axis remodeled cell cycle regulation and rendered resistance to PI3Kα inhibitors in ESCC. Simultaneously targeting PI3Kα and EZH2 may provide an effective strategy for ESCC therapy with high expression of EZH2.

【 授权许可】

Unknown