Aberrant phase separation and cancer

Abstract

Eukaryotic cells are intracellularly divided into numerous compartments or organelles, which coordinate specific molecules and biological reactions. Membrane-bound organelles are physically separated by lipid bilayers from the surrounding environment. Biomolecular condensates, also referred to membraneless organelles, are micron-scale cellular compartments that lack membranous enclosures but function to concentrate proteins and RNA molecules, and these are involved in diverse processes. Liquid-liquid phase separation (LLPS) driven by multivalent weak macromolecular interactions is a critical principle for the formation of biomolecular condensates, and a multitude of combinations among multivalent interactions may drive liquid-liquid phase transition (LLPT). Dysregulation of LLPS and LLPT leads to aberrant condensate and amyloid formation, which causes many human diseases, including neurodegeneration and cancer. Here, we describe recent findings regarding abnormal forms of biomolecular condensates and aggregation via aberrant LLPS and LLPT of cancer-related proteins in cancer development driven by mutation and fusion of genes. Moreover, we discuss the regulatory mechanisms by which aberrant LLPS and LLPT occur in cancer and the drug candidates targeting these mechanisms. Further understanding of the molecular events regulating how biomolecular condensates and aggregation form in cancer tissue is critical for the development of therapeutic strategies against tumorigenesis.

Insight into membraneless organelles and their associated proteins: Drivers, Clients and Regulators

“…LLPS is a tightly regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates, leading to aging-associated diseases [6] , [82] and various neurodegenerative pathologies, among which Alzheimer, Parkinson, Huntington, ALS and FTD diseases stand out [2] , [18] , [68] , [100] . In this work we focus on the nine most representative MLOs comprising at least 15 associated proteins.…”

Liquid–Liquid Phase Separation in the Presence of Macromolecular Crowding and State-dependent Kinetics

“…Recent studies have extended biomolecular condensates to include the postsynaptic density (PSD) in neuronal synapses that regulate synaptic signaling and plasticity [24][25][26][27]. In addition to playing major roles in normal cellular function, the emergent properties from LLPS processes have been implicated in the onset of an array of pathophysiological conditions such as neurodegeneration [11,[28][29][30][31][32][33][34][35][36][37] and carcinogenesis [38,39] due to the aberrant phase separation that triggers protein gelation and aggregation in the condensed phases.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…The presence of redox signaling [ 182 , 183 ] and cancer-related [ 104 , 105 ] proteins in lipid rafts/caveolae further emphasizes the importance of lipid raft domains in health and disease [ 96 , 184 ]. Failure to maintain nanoscopic lipid raft domains with appropriate line tension and membrane elasticity [ 185 ] to functionally host dimerized ATPase [ 186 ], ATP synthase [ 175 ] may contribute to aberrant phase separation, resulting in pathogenic protein aggregates in neurodegeneration [ 11 ] and cancer [ 10 , 12 ].…”

“…Alterations to the glycolytic pathways are often observed during the early stages of neurodegenerative diseases where mitochondrial dysfunction and reduced ATP levels may contribute to protein aggregation [ 515 ]. Increasingly, the pathogenic aggregation of MLOs such as stress granules, p53, FUS, TDP-43, and tau exhibiting dysregulated LLPS is believed to play a major part in the development of neurodegeneration and cancer [ 12 , 516 , 517 , 518 ].…”

“…LLPS creates distinct compartments that enhance or restrict biochemical reactions by enriching or excluding biomolecules from their environment [ 7 ]. Increasing evidence associates diseases such as neurodegeneration and cancer with the formation of protein aggregates from dysregulated, aberrant transitions in phase separation [ 8 , 9 , 10 , 11 , 12 ].…”