Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer

Zheng, Le-Wei; Liu, Cui-Cui; Yu, Ke-Da

doi:10.1186/s13045-023-01522-5

Cited by 14 publications

(4 citation statements)

References 218 publications

(147 reference statements)

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“…Complex biochemical reactions and substance metabolism exist within cancer cells, which may lead to uneven distribution of intracellular substances and the formation of liquid-liquid phase separation (LLPS) of different substances, that is, intracellular LLPS phenomenon. Such a LLPS could ultimately affect cancer proliferation, apoptosis, invasion, metastasis, and treatment sensitivity by influencing cell signaling, gene expression modulation, energy metabolism variation, and other mechanisms [ 1 – 4 ].…”

Section: To the Editormentioning

confidence: 99%

Global research hotspots, development trends and prospect discoveries of phase separation in cancer: a decade-long informatics investigation

Guo,

Feng,

Huang

et al. 2024

Biomark Res

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Liquid-liquid phase separation (LLPS) is a complex and subtle phenomenon whose formation and regulation take essential roles in cancer initiation, growth, progression, invasion, and metastasis. This domain holds a wealth of underutilized unstructured data that needs further excavation for potentially valuable information. Therefore, we retrospectively analyzed the global scientific knowledge in the field over the last decade by using informatics methods (such as hierarchical clustering, regression statistics, hotspot burst, and Walktrap algorithm analysis). Over the past decade, this area enjoyed a favorable development trend (Annual Growth Rate: 34.98%) and global collaboration (International Co-authorship: 27.31%). Through unsupervised hierarchical clustering based on machine learning, the global research hotspots were divided into five dominant research clusters: Cluster 1 (Effects and Mechanisms of Phase Separation in Drug Delivery), Cluster 2 (Phase Separation in Gene Expression Regulation), Cluster 3 (Phase Separation in RNA-Protein Interaction), Cluster 4 (Reference Value of Phase Separation in Neurodegenerative Diseases for Cancer Research), and Cluster 5 (Roles and Mechanisms of Phase Separation). And further time-series analysis revealed that Cluster 5 is the emerging research cluster. In addition, results from the regression curve and hotspot burst analysis point in unison to super-enhancer (a=0.5515, R2=0.6586, p=0.0044) and stress granule (a=0.8000, R2=0.6000, p=0.0085) as the most potential star molecule in this field. More interestingly, the Random-Walk-Strategy-based Walktrap algorithm further revealed that “phase separation, cancer, transcription, super-enhancer, epigenetics”(Relevance Percentage[RP]=100%, Development Percentage[DP]=29.2%), “stress granule, immunotherapy, tumor microenvironment, RNA binding protein”(RP=79.2%, DP=33.3%) and “nanoparticle, apoptosis”(RP=70.8%, DP=25.0%) are closely associated with this field, but are still under-developed and worthy of further exploration. In conclusion, this study profiled the global scientific landscape, discovered a crucial emerging research cluster, identified several pivotal research molecules, and predicted several crucial but still under-developed directions that deserve further research, providing an important reference value for subsequent basic and clinical research of phase separation in cancer.

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Section: To the Editormentioning

confidence: 99%

Global research hotspots, development trends and prospect discoveries of phase separation in cancer: a decade-long informatics investigation

Guo,

Feng,

Huang

et al. 2024

Biomark Res

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“…This membraneless organelle, the nucleolus, is sequestered from the nucleus by liquid droplet formation through LLPS. For the nucleolus and other sub-nuclear organelles, the formation and regulation of LLPS are closely associated with oncogenesis, tumor progression, and metastasis [ 101 , 102 ]. Ide et al used single-molecule tracking to show that RNA polymerase I (Pol I) and chromatin-bound upstream binding factor (UBF) undergo transcription suppression through phase separation [ 39 ].…”

Section: Characteristics and General Functions Of Snornamentioning

confidence: 99%

Subverting the Canon: Novel Cancer-Promoting Functions and Mechanisms for snoRNAs

Huo,

Rai,

Nakatsu

et al. 2024

IJMS

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Small nucleolar RNAs (snoRNAs) constitute a class of intron-derived non-coding RNAs ranging from 60 to 300 nucleotides. Canonically localized in the nucleolus, snoRNAs play a pivotal role in RNA modifications and pre-ribosomal RNA processing. Based on the types of modifications they involve, such as methylation and pseudouridylation, they are classified into two main families—box C/D and H/ACA snoRNAs. Recent investigations have revealed the unconventional synthesis and biogenesis strategies of snoRNAs, indicating their more profound roles in pathogenesis than previously envisioned. This review consolidates recent discoveries surrounding snoRNAs and provides insights into their mechanistic roles in cancer. It explores the intricate interactions of snoRNAs within signaling pathways and speculates on potential therapeutic solutions emerging from snoRNA research. In addition, it presents recent findings on the long non-coding small nucleolar RNA host gene (lncSNHG), a subset of long non-coding RNAs (lncRNAs), which are the transcripts of parental SNHGs that generate snoRNA. The nucleolus, the functional epicenter of snoRNAs, is also discussed. Through a deconstruction of the pathways driving snoRNA-induced oncogenesis, this review aims to serve as a roadmap to guide future research in the nuanced field of snoRNA–cancer interactions and inspire potential snoRNA-related cancer therapies.

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“…Recent advances highlighted that long noncoding RNAs(lncRNAs)plays key regulatory roles in various cellular and molecular mechanisms in cancer progression, through their modulation of protein expression, aggregation, phase separations, enzyme activation and the chromatin regulatory pathway [ 11 – 17 ]. Furthermore, lncRNAs often exhibit tissue-specific expression and are specific to particular cancer types [ 11 , 14 – 16 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

Chen,

Huang,

Zhu

et al. 2024

Exp Hematol Oncol

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Background Mixed-lineage leukemia (MLL) fusion gene caused by chromosomal rearrangement is a dominant oncogenic driver in leukemia. Due to having diverse MLL rearrangements and complex characteristics, MLL leukemia treated by currently available strategies is frequently associated with a poor outcome. Therefore, there is an urgent need to identify novel therapeutic targets for hematological malignancies with MLL rearrangements. Methods qRT-PCR, western blot, and spearman correction analysis were used to validate the regulation of LAMP5-AS1 on LAMP5 expression. In vitro and in vivo experiments were conducted to assess the functional relevance of LAMP5-AS1 in MLL leukemia cell survival. We utilized chromatin isolation by RNA purification (ChIRP) assay, RNA pull-down assay, chromatin immunoprecipitation (ChIP), RNA fluorescence in situ hybridization (FISH), and immunofluorescence to elucidate the relationship among LAMP5-AS1, DOT1L, and the LAMP5 locus. Autophagy regulation by LAMP5-AS1 was evaluated through LC3B puncta, autolysosome observation via transmission electron microscopy (TEM), and mRFP-GFP-LC3 puncta in autophagic flux. Results The study shows the crucial role of LAMP5-AS1 in promoting MLL leukemia cell survival. LAMP5-AS1 acts as a novel autophagic suppressor, safeguarding MLL fusion proteins from autophagic degradation. Knocking down LAMP5-AS1 significantly induced apoptosis in MLL leukemia cell lines and primary cells and extended the survival of mice in vivo. Mechanistically, LAMP5-AS1 recruits the H3K79 histone methyltransferase DOT1L to LAMP5 locus, directly activating LAMP5 expression. Importantly, blockade of LAMP5-AS1-LAMP5 axis can represses MLL fusion proteins by enhancing their degradation. Conclusions The findings underscore the significance of LAMP5-AS1 in MLL leukemia progression through the regulation of the autophagy pathway. Additionally, this study unveils the novel lncRNA-DOT1L-LAMP5 axis as promising therapeutic targets for degrading MLL fusion proteins.

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Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer

Cited by 14 publications

References 218 publications

Global research hotspots, development trends and prospect discoveries of phase separation in cancer: a decade-long informatics investigation

Global research hotspots, development trends and prospect discoveries of phase separation in cancer: a decade-long informatics investigation

Subverting the Canon: Novel Cancer-Promoting Functions and Mechanisms for snoRNAs

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

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