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Updated: Jan 12, 2026
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Class IIa HDACs forced degradation allows resensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer
Vanessa Tolotto1, Nicolò Gualandi1, Ylenia Cortolezzis1
1Laboratory of Biochemistry, Department of Medicine, Università Degli Studi di Udine, Italy.
Abstract:
Epigenetic plasticity and large-scale chromatin remodeling characterize tumor evolution and the emergence of subclones resistant to conventional therapies. Catalytically inactive class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) control the targeted recruitment of chromatin remodeling complexes, making them attractive therapeutic targets in oncology. In this study, we found that HDAC4 is degraded by the proteasome in cancer cells with impaired DNA repair by homologous recombination and after oxaliplatin (OXPT) treatment. Genetic screening identified FBXW7 as the E3 ligase responsible for HDAC4 degradation. FBXW7 loss-of-function mutations are frequently found in patients with colorectal cancer (CRC) and were found associated with the development of resistance to OXPT. Forced degradation of Class IIa HDACs using a PROTAC-based compound restored OXPT sensitivity in FBXW7-mutated CRC cells, patient-derived organoids (PDOs), and mice. Mechanistically, removal of HDAC4 in FBXW7-mutated CRC treated with OXPT recreated an epigenetic state comparable to OXPT-sensitive cells. Furthermore, patient profiling based on the epigenetic state of the super-enhancers controlled by HDAC4 successfully identified a priori CRC patients resistant to platinum. This study supports HDAC4 as a key mediator of oxaliplatin resistance in FBXW7-mutated CRC and highlights the remodeling of a well-defined super-enhancer repertoire as part of the process of OXPT resensitization.
Insights
Histone deacetylase 4 (HDAC4) degradation drives resistance to oxaliplatin in colorectal cancer with FBXW7 mutations. Restoring HDAC4 levels resensitizes tumors to this chemotherapy, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Tumor evolution involves epigenetic plasticity and chromatin remodeling, leading to therapy resistance.
- Class IIa histone deacetylases (HDACs) regulate chromatin remodeling and are potential oncology targets.
- Oxaliplatin (OXPT) resistance is a significant challenge in colorectal cancer (CRC) treatment.
Purpose of the Study:
- Investigate the role of HDAC4 in OXPT resistance in CRC.
- Identify mechanisms of HDAC4 regulation and potential therapeutic interventions.
- Develop biomarkers for predicting OXPT response.
Main Methods:
- Proteasomal degradation assays for HDAC4.
- Genetic screening to identify E3 ligase involved in HDAC4 degradation.
- PROTAC technology for targeted protein degradation.
- Analysis of patient-derived organoids (PDOs) and mouse models.
- Epigenetic profiling of super-enhancers.
- CRC patient data analysis.
Main Results:
- HDAC4 is degraded by the proteasome in OXPT-treated cancer cells with impaired DNA repair.
- FBXW7 was identified as the E3 ligase responsible for HDAC4 degradation.
- FBXW7 loss-of-function mutations, common in CRC, correlate with OXPT resistance.
- PROTAC-mediated degradation of Class IIa HDACs restored OXPT sensitivity in resistant CRC models.
- HDAC4 removal in resistant cells mimicked the epigenetic state of sensitive cells.
- Epigenetic profiling of HDAC4-controlled super-enhancers identified OXPT-resistant patients.
Conclusions:
- HDAC4 is a key mediator of OXPT resistance in FBXW7-mutated CRC.
- Targeting HDAC4 degradation presents a therapeutic strategy to overcome OXPT resistance.
- Remodeling of super-enhancers by HDAC4 is crucial for OXPT resensitization.
- Epigenetic biomarkers based on HDAC4 activity can predict platinum response in CRC.
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