Targeting the interplay between biomolecular condensates and regulatory RNAs in cancer

Biomolecular condensates (BCs), RNA–protein complexes, have emerged as potential therapeutic targets for various cellular pathologies, including cancer. The mechanisms underlying liquid–liquid phase separation rely on the properties of proteins with intrinsically disordered regions and prion-like domains, which drive phase separation in conjunction with their RNA partners. These ribonucleoprotein complexes are distinct in their localization, compartmentalization, epigenetic regulation, and dynamics. BCs are categorized as either nuclear—such as promyelocytic leukemia nuclear bodies, speckles, paraspeckles, and Cajal bodies—or cytosolic, including stress granules (SGs), P bodies, and U bodies. Regulatory RNAs, assembled with protein partners through phase separation, exhibit oncogenic properties and perform key biological functions, including gene transcription, euchromatin/heterochromatin formation, mRNA splicing, mRNA translation, protein compartmentalization, and degradation. Epitranscriptome-modifying enzymes regulate the stability and oncogenic potential of noncoding RNAs (ncRNAs). These RNAs, along with their associated epitranscriptomic and protein modifications, play critical roles in the functioning and dissolution of condensates. Recent advancements in cancer therapy have focused on developing drugs targeting the epitranscriptomic machinery, including the writers, readers, and erasers of RNA modifications. Therapeutic strategies aim to target oncogenic RNAs, tumor-promoting proteins, and RNA–protein interaction domains. Several cancer therapeutic compounds have been developed using the PROTAC and RIBOTAC approaches. Moreover, small molecules targeting protein–RNA interactions and antisense oligonucleotides have been developed. Promising avenues in cancer therapeutics involve the inhibition of ncRNAs and their associated protein complexes, modulation of BCs, regulation of SGs and paraspeckles, and development of small molecule compounds with potential applications across various cancer types.