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.
Highlights
Malignant breast cancers such as triple-negative breast cancer (TNBC) often cause clinical drug resistance, and there is no suitable drug targets [1, 2]
We discovered that small-molecule inhibitor of histone deacetylase (HDAC), Trichostatin A (TSA), significantly enhanced the expression of checkpoint with forkhead and ring finger domains (CHFR) protein though directly binding to CHFR, which is independent of HDAC enzymatic activity
CHFR interacts and negatively correlates with Zinc finger E-box-binding homeobox 1 (ZEB1) We previously found that ZEB1 is highly expressed in breast cancers [12] and confers basal breast cancer resistant to conventional chemotherapy and neoadjuvant therapy (Fig. S1a–d)
Summary
Malignant breast cancers such as triple-negative breast cancer (TNBC) often cause clinical drug resistance, and there is no suitable drug targets [1, 2]. Zinc finger E-box-binding homeobox 1 (ZEB1) protein is a key transcriptional factor that induces epithelial–mesenchymal transition and cellular plasticity in cancer cells [4,5,6,7,8]. ZEB1 has been reported to transform non-invasive breast cancer cells into highly malignant cancer stem cells (CSCs) [9, 10]. We and others recently demonstrate that ZEB1 protein can promote the resistance of breast cancer to radiotherapy and chemotherapy [10,11,12,13,14]. The inactivating signals or regulators that make ZEB1 protein quickly disappear remain unclear. We conduct an integrated analysis to identify a ZEB1-binding E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR)
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