EZH2 Inhibition Enhances PD‐L1 Protein Stability Through USP22‐Mediated Deubiquitination in Colorectal Cancer

• DOI: 10.1002/advs.202308045
• Publication Date: 2024-03-23T06:12:45Z
• Authors: Jiaqi Huang; Qianqian Yin; Yuqing Wang; Xin Zhou; Yunyun Guo; Yuanjun Tang; Rui Cheng; Xiaotong Yu; Jie Zhang; Chen Huang; Zhanya Huang; Jianlin Zhang; Zhengyang Guo; Xiao Huo; Yan Sun; Yanfang Li; Hao Wang; Jianling Yang; Lixiang Xue
• Keywords: Immune checkpoint; Cancer Immunotherapy; Deubiquitinating enzyme

Abstract The regulation of PD‐L1 is the key question, which largely determines outcome immune checkpoint inhibitors (ICIs) based therapy. However, besides transcription level, protein stability closely correlated with its function and has drawn increasing attention. In this study, EZH2 inhibition enhances expression stability, deubiquitinase ubiquitin‐specific peptidase 22 (USP22) identified as a mediator in process. transcriptionally upregulates USP22 expression, upregulated further stabilizes PD‐L1. Importantly, combination anti‐PD‐1 blockade therapy improves tumor microenvironment, sensitivity to immunotherapy, exerts synergistic anticancer effects. addition, knocking down can potentially enhance therapeutic efficacy on colon cancer. These findings unveil novel role evasion by upregulating PD‐L1, drawback be compensated combining ICI immunotherapy. Therefore, these provide valuable insights into EZH2‐USP22‐PD‐L1 regulatory axis, shedding light optimization both inhibitor‐based epigenetic therapies achieve more efficacies accuracy cancer treatment.