Super-enhancers reorganization controls re-sensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer

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 proteasomal degraded in cancer cells impaired in DNA repair by homologous recombination. Genetic screening identified FBXW7 as the E3 ligase responsible for this degradation. FBXW7 loss-of-function mutations are frequently found in patients with colorectal cancer (CRC) and associated with the development of resistance to Oxaliplatin. Forced degradation of HDAC4 using a PROTAC-based compound restored oxaliplatin sensitivity in FBXW7-mutated CRC cells, patient-derived organoids (PDOs) and in mice. Mechanistically, removal of HDAC4 in FBXW7-mutated CRC cells and PDOs treated with oxaliplatin resulted in a profound restructuring of the super-enhancer landscape by restoring a super-enhancer repertoire typical of Oxaliplatin-sensitive cells. Furthermore, patient profiling based on the epigenetic state of super-enhancers controlled by HDAC4 successfully identifies a priori CRC patients resistant to platinum. This study supports HDAC4 as a key mediator of oxaliplatin resistance in FBXW7-mutated CRC and underlines the remodeling of a well-defined repertoire of super-enhancers as part of the process of re-sensitization.