Protein phase separation: A novel therapy for cancer?

Wang, Wei; Chen, Yingqian; Xu, Aixiao; Cai, Minyi; Cao, Ji; Zhu, Hong; Yang, Bo; Shao, Xuejing; He, Qiaojun

doi:10.1111/bph.15242

Cited by 17 publications

(16 citation statements)

References 164 publications

(324 reference statements)

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“…Recent studies explain these distribution difference-induced activity variations by the ‘phase separation’ theory [ 64 , 65 ]. Different aggregation states of proteins caused by phase separation could affect various protein functions and biological processes [ 66 – 68 ]. Clip170 comets are also reported to be similar to phase-separated liquid condensates [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Tension of plus-end tracking protein Clip170 confers directionality and aggressiveness during breast cancer migration

Xie

et al. 2022

Cell Death Dis

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The microtubule (MT) plus-end binding protein Clip170 is associated closely with breast cancer invasion and migration. In this study, Clip170 tension observed by a newly designed cpstFRET tension probe was suggested to be positive related to breast cancer aggressiveness, which could be regulated by α-tubulin detyrosination-induced MT disassembly. Clip170 phosphorylation induced by Ribosomal protein S6 kinase (RSK) could also increase its tension and promote the conversion of a discrete comet-like Clip-170 distribution into a spotty pattern during cancer metastasis. Heightened Clip170 tension was correlated with the formation of cortactin-associated filopodia and lamellipodia, and then promoted invasion and metastasis both in vitro and in vivo. Meanwhile, Clip170 tension enhanced at the leading edge in directional migration, accompanying with IQGAP1 subcellular distribution variation. Our work indicates that the malignancy and directionality during breast cancer migration depend on the magnitude and polarization of Clip170 tension, and we suggest Clip170 tension as a new potential drug target for breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Tension of plus-end tracking protein Clip170 confers directionality and aggressiveness during breast cancer migration

Xie

et al. 2022

Cell Death Dis

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“…The spatiotemporal interactions between protein and nucleic acid are weak interactions controlled by dynamic post-translational modifications (such as phosphorylation, acetylation, and methylation) and RNA modifications (such as m 6 A modification) [ 286 ]. In cancer cells, the functional phase separation can condensate cancer-related proteins, involved in genomic instability, transcriptional regulation of cancer-related proteins/pathways, and protein degradation (see reviews by Jiang et al and Wang et al, who summarised the oncogenic processes involved in phase separation [ 286 , 287 ]).…”

Section: Key Structural Elements Mediating 3d Chromatin Interactionsmentioning

confidence: 99%

3D chromatin architecture and transcription regulation in cancer

2022

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Chromatin has distinct three-dimensional (3D) architectures important in key biological processes, such as cell cycle, replication, differentiation, and transcription regulation. In turn, aberrant 3D structures play a vital role in developing abnormalities and diseases such as cancer. This review discusses key 3D chromatin structures (topologically associating domain, lamina-associated domain, and enhancer–promoter interactions) and corresponding structural protein elements mediating 3D chromatin interactions [CCCTC-binding factor, polycomb group protein, cohesin, and Brother of the Regulator of Imprinted Sites (BORIS) protein] with a highlight of their associations with cancer. We also summarise the recent development of technologies and bioinformatics approaches to study the 3D chromatin interactions in gene expression regulation, including crosslinking and proximity ligation methods in the bulk cell population (ChIA-PET and HiChIP) or single-molecule resolution (ChIA-drop), and methods other than proximity ligation, such as GAM, SPRITE, and super-resolution microscopy techniques.

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“…Although the formation of non-infectious, self-assembled macromolecular complexes represents a vital physiological function, these assemblies are highly susceptible to the formation of pathological aggregates that are now associated with cancer [ 252 , 253 , 254 ] and neurodegenerative disorders. Cancer is now recognized as a disease that may result from aberrant LLPS and aggregation of MLOs [ 252 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 ]. Wild-type human tumor suppressor protein p53 expressed in yeast undergoes LLPS induced by multivalent interactions between its intrinsically disordered N- and C-termini to form unstable droplets that dissolve quickly when stress is removed.…”

Section: Liquid–liquid Phase Separation May Regulate Prion Conversion...mentioning

confidence: 99%

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Loh¹,

Reíter

2022

Molecules

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The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

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Protein phase separation: A novel therapy for cancer?

Cited by 17 publications

References 164 publications

Tension of plus-end tracking protein Clip170 confers directionality and aggressiveness during breast cancer migration

Tension of plus-end tracking protein Clip170 confers directionality and aggressiveness during breast cancer migration

3D chromatin architecture and transcription regulation in cancer

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

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