Histone chaperones as potential epidrug targets against cancer

Abstract

Epigenetic modifications play a crucial role in various diseases, including cancer. Targeting chromatin modulators to normalize these epigenetic markers is a promising avenue for overcoming cancer drug resistance and improving treatment efficacy. Histone chaperones, implicated in cancer due to their imperfect compensatory mechanisms, represent potential targets for epidrugs. To identify these targets, we performed enrichment and network analyses of histone chaperone interactions, both among themselves and with other proteins. This approach provided insights into structure-function relationships. The selective binding of histone chaperones to canonical histones highlights their potential as epidrugs targets. Network analysis of common histone chaperones identified key hub proteins: HSP90AB1, RBBP4, NPM1, DAXX, and SET. These hub proteins, particularly RBBP4, which formed the largest protein cluster was found associated with oncogenesis, suggesting RBBP4 as prime candidates for therapeutic intervention. Druggability prediction of these hub protein pockets further identified RBBP4 as the most promising target, with Ritonavir emerging as a potential epidrugs. These findings provide a crucial foundation for future epidrugs discovery targeting cancer.