Liquid–liquid phase separation in tumor biology

Abstract

Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins and nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response and repair, transcription, and signal transduction. Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer, and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology. In this review, we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS. In addition, we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.

Targeting phase separation on enhancers induced by transcription factor complex formations as a new strategy for treating drug-resistant cancers

“…Several factors have been shown to modulate physiochemical features of condensates such as the viscoelasticity and condensate structure ( 7 , 8 , 52 ).…”

“…As LLPS depens on the concentration of macromolecules, the threshold concentrations are essential factors of LLPS ( 38 ). When the concentration of macromolecules in the solution is increased to the limit of solubility, the threshold concentration, the interactions between the macromolecules will become strong and this solution will have propensity to LLPS ( 52 ). The threshold concentration is determined by several biophysical parameters including the salt concentration, temperature, and other ions ( 8 ).…”

“…In addition, long non-coding RNAs (lncRNAs) are localized on chromatin and form a cluster of RNA in a particular nuclear region for transcriptional regulation ( 7 , 8 ). Many findings have demonstrated that NEAT1 lncRNAs can functions as a scaffold RNA and selectively interacts with NONO/SFPQ proteins, which dynamically oligomerize proteins for LLPS to facilitate the assembly of paraspeckle ( 52 ).…”

“…Protein concentration, posttranslational modifications (PTMs) of environmental elements provide a major mechanism for the regulation ( 7 , 52 ). Emerging evidence suggests that PTMs, such as phosphorylation, acetylation, methylation, and SUMOylation, have important roles in regulating LLPS.…”

“…For example, Arg methylation mediated by protein arginine methyltransferase (PRMT1) increases the rate of SG formation caused by oxidative stress ( 59 ). SUMOylation of PMLs contributes significantly to the formation of the PML nuclear body, whereas de-SUMOylation can lead to a constituent protein being released and nuclear bodies being separated during mitosis ( 52 ). Moreover, three distinct IDRs in G3BP1 regulates its properties for enhancing LLPS.…”