: 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.
