The Burgeoning Significance of Liquid-Liquid Phase Separation in the Pathogenesis and Therapeutics of Cancers

Abstract

Liquid-liquid phase separation (LLPS) is a physiological phenomenon that parallels the mixing of oil and water, giving rise to compartments with diverse physical properties. Biomolecular condensates, arising from LLPS, serve as critical regulators of gene expression and control, with a particular significance in the context of malignant tumors. Recent investigations have unveiled the intimate connection between LLPS and cancer, a nexus that profoundly impacts various facets of cancer progression, including DNA repair, transcriptional regulation, oncogene expression, and the formation of critical membraneless organelles within the cancer microenvironment. This review provides a comprehensive account of the evolution of LLPS from the molecular to the pathological level. We explore the mechanisms by through which biomolecular condensates govern diverse cellular physiological processes, encompassing gene expression, transcriptional control, signal transduction, and responses to environmental stressors. Furthermore, we concentrate on potential therapeutic targets and the development of small-molecule inhibitors associated with LLPS in prevalent clinical malignancies. Understanding the role of LLPS and its interplay within the tumor milieu holds promise for enhancing cancer treatment strategies, particularly in overcoming drug resistance challenges. These insights offer innovative perspectives and support for advancing cancer therapy.

Keywords: biomolecular condensates; cancer; disease; liquid-liquid phase separation; super enhancer.

Figure 1

History of the discovery and development of LLPS. Representative milestone findings promoting the development of LLPS are enumerated in the figure. LLPS, liquid-liquid phase separation; PML, promyelocytic leukemia.

Figure 2

Functions of biomolecular condensates. Biomolecular condensates are involved in nuclear functions and are critical for DNA damage, nuclear translocation, enzymatic reactions, amplification, transcription, translation, and post-translational modification processes. Condensates are involved in signal transduction, stress sensing, and transport processes. A. Model of a phases-separated complex at gene regulatory elements. At the super-enhancer locus, transcriptional regulators with extensive interactions, including TFs, BRD4, MED1, and RNA pol II, are enriched to form a phase-separated condensate, which is separated from others. B. Post-translational modification processes such as phosphorylation, acetylation, ubiquitination, and SUMOylation. C. Among the FG-nucleoporins form the central pore of the nuclear pore complexes, which governs the nucleocytoplasmic transport through the pores. D. Condensates are involved in signal transduction. E. Condensates are involved in stress response. F. After DNA damage sites cause the formation of γH2AX and recruitment of MDC1 for nucleation, 53BP1 accumulates and phase separates, and P53 acts as a scaffold for client molecules, interacting transiently with 53BP1, where they find an environment permissive for their activation. G. Phase separation significantly accelerates the efficiency of multienzyme biocatalysis. BRD4, bromodomain-containing protein; RNA Pol II, RNA polymerase II; MED1, mediator complex subunit 1; TF, transcription factors. Me, methylation; P, phosphorylation; Ac, acetylation; Su, and small ubiquitin-like modifier; FG, Phenylalanine-glycine-rich; SGs, stress granules; 53PB1, p53 binding protein 1; γH2AX, phosphorylated histone H2AX; MDC1, Mediator of DNA damage checkpoint protein 1.

Figure 3

Small molecule inhibitors related to LLPS in prevalent clinical malignancies. These diseases include glioblastoma, breast cancer, sarcoma, colorectal cancer, ovarian cancer, leukemia, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, and osteosarcoma cancer. ACP-1n, aminocyclopropenone 1n; EVG, elvitegravir; HDACi, histone deacetylase inhibitor; LSD 1i, lysine-specific histone demethylase 1 inhibitor; SARICA, small-molecule-selective AR-irreversible covalent antagonists.