2. Academic Validation
  3. BRD7 suppresses tumor chemosensitivity to CHK1 inhibitors by inhibiting USP1-mediated deubiquitination of CHK1

BRD7 suppresses tumor chemosensitivity to CHK1 inhibitors by inhibiting USP1-mediated deubiquitination of CHK1

  • Cell Death Discov. 2023 Aug 25;9(1):313. doi: 10.1038/s41420-023-01611-x.
Lemin Li # 1 2 3,  Linchen Wang # 1 2 3,  Dian Liu 1 2 3,  Yongchao Zhao 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. yongchao@zju.edu.cn.
  • 5 Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. yongchao@zju.edu.cn.
  • 6 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. yongchao@zju.edu.cn.
  • 7 Cancer Center, Zhejiang University, Hangzhou, China. yongchao@zju.edu.cn.
  • # Contributed equally.
PMID: 37626049 DOI: 10.1038/s41420-023-01611-x
Abstract

Checkpoint kinase 1 (Chk1), a key effector in the cellular response to DNA lesions, is a crucial component of all cell cycle checkpoints. Recent reports have revealed that Chk1 is highly expressed in numerous Cancer types in the clinical settings. However, the mechanisms underlying the regulation of Chk1 expression in tumor cells remain unclear. Here, we report that Chk1 is negatively regulated by the bromodomain-containing protein 7 (BRD7). Specifically, BRD7 silencing increased Chk1 (but not Chk2) expression at both mRNA and protein levels, in a p53-independent manner in multiple tumor cell lines. Furthermore, BRD7 silencing stabilized Chk1 via reducing its ubiquitination. Mechanistically, BRD7 knockdown not only increased the levels of USP1, a Deubiquitinase for Chk1, but also promoted the interaction between Chk1 and USP1, subsequently enhancing the de-ubiquitination of Chk1. USP1 knockdown abrogated BRD7 silencing-induced Chk1 induction. Biologically, the increased expression of Chk1 in tumor cells caused by BRD7 silencing significantly increased cell sensitivity to Chk1 inhibitors by enhancing tumor cell Apoptosis, and this effect was reversed by the simultaneous knockdown of Chk1 or USP1. Taken together, our findings suggest that BRD7 is a potential genetic or drug target that may help to improve the efficacy of chemotherapeutic drugs targeting Chk1 in combinatorial therapy.

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