Super-enhancers reorganization controls re-sensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer
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) act as acetyl-lysine readers that form the scaffold for the targeted recruitment of chromatin remodeling complexes, making them very attractive therapeutic targets in the field of 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 FBXW7 mutation status is associated with the development of resistance to oxaliplatin. Deletion of HDAC4 or its forced degradation with a PROTAC-based compound restored oxaliplatin sensitivity in FBXW7-mutated CRC cells, patient-derived organoids (PDOs) and xenografts, with no effect on DNA damage response activation or DNA platination. Mechanistically, forced removal of HDAC4 in FBXW7-mutant CRC cells and PDOs treated with oxaliplatin resulted in a deep rearrangement of the super-enhancer landscape, with a dramatic loss of super-enhancers found in oxalipaltin-resistant samples and restoration of certain super-enhancers found in oxaliplatin-sensitive cells. The disassembly of HDAC4 complexes achieved with Tasquinimod partially recapitulated the effects obtained with the PROTAC-based HDAC4 compound, demonstrating the importance of the epigenetic function of HDAC4 in supporting drug resistance. This study supports HDAC4 as a key mediator of oxaliplatin resistance in FBXW7-mutated CRC and highlights the remodeling of a well-defined repertoire of super-enhancers as part of the process of successful re-sensitization. Overall design: RNA was extracted from HCT-116 cells, WT or KO for FBXW7, and transfected for 48h with esiRNAs directed against CT or HDAC4 or treated with PROTAC compound #11 directed against HDAC4. Cells were treated or not for the last 24h with OxPt (50 µM).