The roles of chromatin remodeling and 3D genome organization in cancers: from mechanistic insights to emerging treatment options

Abstract

Abstract Chromatin remodeling comprises a set of molecular mechanisms that regulate gene transcription, DNA replication, and DNA repair by altering nucleosome structure. Previous studies have found that chromatin remodelers are heavily mutated in cancer patients, and targeting aberrant chromatin remodeling activities holds great potential for clinical benefit. Despite these promising findings, several significant hurdles remain before this strategy can be successfully transitioned from bench to bedside. The classic concept of chromatin remodeling focuses on the linear 2D chromatin structural level. While the emergence of sophisticated sequencing modalities has underscored the significance of 3D chromatin architecture, the mechanistic underpinnings and broader implications for cancer biology continue to be largely elusive. This review provides a comprehensive synthesis of the mechanisms and functional roles of classical chromatin remodelers within both physiological and neoplastic contexts. Furthermore, we integrate emerging insights regarding the cohesin complex as a primary mediator of three-dimensional (3D) genomic organization. By proposing a hierarchical framework that distinguishes between 'first-level' (classical) and 'higher-order' chromatin remodeling, we aim to provide a more holistic understanding of the integrated regulatory networks governing chromatin architecture. Furthermore, we have systematically cataloged the landscape of therapeutic strategies targeting chromatin remodelers in oncology. By evaluating the divergence between clinically approved therapies and those currently in developmental pipelines, we delineate the primary challenges confronting the field and propose strategic directions for future research. Collectively, we have delineated the multifaceted contributions of chromatin remodeling to cancer progression. The strategic modulation of these remodeling processes represents a vital frontier in the development of novel therapeutic interventions and is likely to emerge as a primary focus for future cancer management strategies.