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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\u2010of\u2010function 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\u2010based compound restored OXPT sensitivity in FBXW7\u2010mutated CRC cells, patient\u2010derived organoids (PDOs), and mice. Mechanistically, removal of HDAC4 in FBXW7\u2010mutated CRC treated with OXPT recreated an epigenetic state comparable to OXPT\u2010sensitive cells. Furthermore, patient profiling based on the epigenetic state of the super\u2010enhancers controlled by HDAC4 successfully identified\n                    <jats:italic>a priori<\/jats:italic>\n                    CRC patients resistant to platinum. This study supports HDAC4 as a key mediator of oxaliplatin resistance in FBXW7\u2010mutated CRC and highlights the remodeling of a well\u2010defined super\u2010enhancer repertoire as part of the process of OXPT resensitization.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70152","type":"journal-article","created":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T04:24:38Z","timestamp":1761971078000},"page":"637-667","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Class\n                    <scp>IIa HDACs<\/scp>\n                    forced degradation allows resensitization\u00a0of oxaliplatin\u2010resistant\n                    <scp>FBXW7<\/scp>\n                    \u2010mutated colorectal cancer"],"prefix":"10.1002","volume":"20","author":[{"given":"Vanessa","family":"Tolotto","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry, Department of Medicine Universit\u00e0 Degli Studi di 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