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CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1.

Authors
  • Luo, Hong1
  • Zhou, Zhicheng2
  • Huang, Shan1
  • Ma, Mengru1
  • Zhao, Manyu1
  • Tang, Lixu3
  • Quan, Yuan4
  • Zeng, Yiming5
  • Su, Li1
  • Kim, Jongchan6
  • Zhang, Peijing7
  • 1 National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Tongji Hospital, Huazhong University of Science and Technology, 430074, Wuhan, China. , (China)
  • 2 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 3 School of Martial Arts, Wuhan Sports University, 430079, Wuhan, China. , (China)
  • 4 Stem Cell Laboratory, the Second Affiliated Hospital, Fujian Medical University, 362000, Quanzhou, China. [email protected] , (China)
  • 5 Stem Cell Laboratory, the Second Affiliated Hospital, Fujian Medical University, 362000, Quanzhou, China. , (China)
  • 6 Department of Life Science, Sogang University, Seoul, 04107, Republic of Korea. , (North Korea)
  • 7 National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Tongji Hospital, Huazhong University of Science and Technology, 430074, Wuhan, China. [email protected] , (China)
Type
Published Article
Journal
Cell Death and Disease
Publisher
Springer Nature
Publication Date
Aug 30, 2021
Volume
12
Issue
9
Pages
820–820
Identifiers
DOI: 10.1038/s41419-021-04114-8
PMID: 34462429
Source
Medline
Language
English
License
Unknown

Abstract

Failures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers. © 2021. The Author(s).

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