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Innovation: The Wei Li research group of the Hershey Medical Research Center of Pennsylvania State University used the BioID biotin intracellular protein labeling technology to identify and analyze the key protein NONO that interacts with the core transcriptional activator protein TAZ of the Hippo signaling pathway
.
This study confirmed for the first time that NONO protein and TAZ protein form a liquid-liquid phase separation structure in the nucleus, which has an important regulatory effect on the activation of TAZ/Tead associated with glioma tumorigenesis (Figure 1)
.
At the same time, the study clarified the function and regulatory molecular mechanism of NONO in the Hippo signaling pathway that mediates TAZ/Tead transcription, and provides a new target for studying the occurrence and development of glioma and cancer treatment
.
Keywords: Advanced Science, TAZ, NONO, Hippo signaling pathway, liquid-liquid separation, transcription regulation, glioma (Figure 1) Hippo signaling pathway regulates the size, development, regeneration, and carcinogenesis of multicellular organisms Evolutionary conservative signaling pathways
.
Its abnormalities are closely related to the occurrence and development of tumors, including regulating tumor cell proliferation, survival, and tumor stem cell characteristics [1]
.
Therefore, studying the molecular regulation mechanism of the Hippo signaling pathway and uncovering the secrets of Hippo signaling gene expression regulation is crucial to understanding the occurrence and treatment of malignant tumor diseases
.
Glioma is the most common and fatal primary tumor of the central nervous system, accounting for about 80% of central nervous system malignant tumors [2]
.
According to its degree of invasion, gliomas can be divided into low-grade (grade I and II) and high-grade (grade III and IV), and many literatures reported that the downstream core regulatory protein TAZ of the Hippo signaling pathway is involved in gliomas.
Overexpression, especially in high-grade malignant gliomas, causes intranucleus accumulation, which is closely related to the prognosis and survival of patients, and is also a core regulator of brain tumor mesenchymal stem cells [3]
.
The downstream effector of the Hippo pathway, YAP/TAZ, promotes cell growth, survival and stem cell regulation of gene transcription by accumulating in the nucleus [4]
.
However, after YAP/TAZ accumulates in the nucleus, how to activate the molecular mechanism of transcriptional regulation of gene expression is still unclear
.
In recent years, studies have found that there are a large number of liquid-phase membraneless compartments in eukaryotic cells.
These membraneless compartments are caused by the condensation of biological macromolecules such as DNA and proteins to cause "liquid-liquid" phase separation (liquid-liquid phase separation).
, LLPS), it participates in many physiological processes such as cell signal transduction and gene expression regulation, and the disorder of LLPS structure is closely related to the occurrence and development of neurodegenerative diseases and tumors [5]
.
Recent studies have shown that phase separation is a molecular regulation mechanism of "transcription aggregates" [6]
.
The latest research reports that both YAP and TAZ can form liquid-liquid separation in the nucleus.
By participating in super-enhancers and distinguishing from multiple key cofactors to form a phase separation similar to a "transcription aggregate" to promote gene transcription, the key is Cofactors mainly include TEAD, BRD4, MED1, CDK9 and RNA Pol II [7, 8]
.
However, how the TAZ protein forms LLPS in cells and its regulatory mechanism are still unknown
.
The study used glioma cells as a model and used BioID biotin intracellular protein labeling technology to screen and identify the key protein NONO that directly interacts with the core protein TAZ of the Hippo signaling pathway
.
Previous studies reported that NONO is the core component of the paraspeckle protein in the nucleus, and the other two paraspeckle proteins PSF/SFPQ, PSPC1 in the form of a heterodimer, plays an important role in organ development, innate immunity, and tumors [9 ]
.
In this study, it was found that NONO is a new TAZ-specific interacting protein, while the other two paraspeckle proteins (PSF/SFPQ, PSPC1) do not interact with TAZ
.
Studies have also shown that NONO can mediate the transcriptional activation of TAZ LLPS and TAZ/Tead in the nucleus; at the same time, the interaction between TAZ/NONO and TAZ/TEAD regulates TAZ-mediated target genes CTGF and CYR61 in different time and space.
Expression
.
Knockout of NONO significantly reduces nuclear TAZ LLPS, while overexpression of NONO promotes TAZ’s LLPS; at the same time knocking out NONO also significantly reduces the interaction of TAZ with TEAD, Rpb1 (the main component of RNA Pol II) and enhancers (Picture 1)
.
In addition, the study found that the degree of tumor malignancy was positively correlated with the high expression of NONO by examining the specimens of glioma patients, and the high expression of NONO and TAZ significantly shortened the prognostic survival of GBM patients
.
In the orthotopic glioblastoma mouse model, reducing NONO expression significantly inhibited TAZ-driven tumorigenesis and prolonged the survival time of mice
.
Therefore, this study shows that NONO, as an intranuclear factor, promotes the oncogenic transcriptional program driven by TAZ LLPS and TAZ
.
These findings provide potential drug targets for keratoblastoma and have important clinical significance for the treatment of this tumor
.
The results of the study were published in the journal Advanced Science in October 2021
.
Associate Professor Wei Li of the Hershey Medical Research Center of Pennsylvania State University is the corresponding author of the study.
Assistant Professor Wei Yiju of his research group and Assistant Professor Luo Huacheng of Professor Suming Huang's research group are the co-first authors of the research
.
WILEY paper information: The paraspeckle protein NONO promotes TAZ phase separation in the nucleus to drive glioblastoma oncogenic transcriptional program.
Yiju Wei#, Huacheng Luo#, Patricia Yee, Lijun Zhang, Zhijun Liu, Haiyan Zheng, Lei Zhang, Benjamin Anderson, Miaolu Tang , Suming Huang, and Wei Li*.
Advanced Science DOI: 10.
1002/advs.
202102653 Click "Read the original text" in the lower left corner to view the original text of the paper
.
Introduction to AdvancedScience Journal "Advanced Science" (Advanced Science) Wiley is a high-quality open source journal founded in 2014.
It publishes innovative achievements and cutting-edge progress in various fields such as materials science, physical chemistry, biomedicine, and engineering
.
The journal is dedicated to disseminating scientific research results to the public to the greatest extent, and all articles are freely available
.
The latest impact factor is 16.
806, and the 2020 SCI journals of the Chinese Academy of Sciences will be divided into the Q1 area of the material science category and the Q1 area of the engineering technology category
.
Press and hold the QR code on the official WeChat platform of AdvancedScienceNewsWiley's scientific research information.
Follow us to share cutting-edge information｜Focus on scientific research trends to publish scientific research news or apply for information sharing, please contact: ASNChina@Wiley.
com
.
This study confirmed for the first time that NONO protein and TAZ protein form a liquid-liquid phase separation structure in the nucleus, which has an important regulatory effect on the activation of TAZ/Tead associated with glioma tumorigenesis (Figure 1)
.
At the same time, the study clarified the function and regulatory molecular mechanism of NONO in the Hippo signaling pathway that mediates TAZ/Tead transcription, and provides a new target for studying the occurrence and development of glioma and cancer treatment
.
Keywords: Advanced Science, TAZ, NONO, Hippo signaling pathway, liquid-liquid separation, transcription regulation, glioma (Figure 1) Hippo signaling pathway regulates the size, development, regeneration, and carcinogenesis of multicellular organisms Evolutionary conservative signaling pathways
.
Its abnormalities are closely related to the occurrence and development of tumors, including regulating tumor cell proliferation, survival, and tumor stem cell characteristics [1]
.
Therefore, studying the molecular regulation mechanism of the Hippo signaling pathway and uncovering the secrets of Hippo signaling gene expression regulation is crucial to understanding the occurrence and treatment of malignant tumor diseases
.
Glioma is the most common and fatal primary tumor of the central nervous system, accounting for about 80% of central nervous system malignant tumors [2]
.
According to its degree of invasion, gliomas can be divided into low-grade (grade I and II) and high-grade (grade III and IV), and many literatures reported that the downstream core regulatory protein TAZ of the Hippo signaling pathway is involved in gliomas.
Overexpression, especially in high-grade malignant gliomas, causes intranucleus accumulation, which is closely related to the prognosis and survival of patients, and is also a core regulator of brain tumor mesenchymal stem cells [3]
.
The downstream effector of the Hippo pathway, YAP/TAZ, promotes cell growth, survival and stem cell regulation of gene transcription by accumulating in the nucleus [4]
.
However, after YAP/TAZ accumulates in the nucleus, how to activate the molecular mechanism of transcriptional regulation of gene expression is still unclear
.
In recent years, studies have found that there are a large number of liquid-phase membraneless compartments in eukaryotic cells.
These membraneless compartments are caused by the condensation of biological macromolecules such as DNA and proteins to cause "liquid-liquid" phase separation (liquid-liquid phase separation).
, LLPS), it participates in many physiological processes such as cell signal transduction and gene expression regulation, and the disorder of LLPS structure is closely related to the occurrence and development of neurodegenerative diseases and tumors [5]
.
Recent studies have shown that phase separation is a molecular regulation mechanism of "transcription aggregates" [6]
.
The latest research reports that both YAP and TAZ can form liquid-liquid separation in the nucleus.
By participating in super-enhancers and distinguishing from multiple key cofactors to form a phase separation similar to a "transcription aggregate" to promote gene transcription, the key is Cofactors mainly include TEAD, BRD4, MED1, CDK9 and RNA Pol II [7, 8]
.
However, how the TAZ protein forms LLPS in cells and its regulatory mechanism are still unknown
.
The study used glioma cells as a model and used BioID biotin intracellular protein labeling technology to screen and identify the key protein NONO that directly interacts with the core protein TAZ of the Hippo signaling pathway
.
Previous studies reported that NONO is the core component of the paraspeckle protein in the nucleus, and the other two paraspeckle proteins PSF/SFPQ, PSPC1 in the form of a heterodimer, plays an important role in organ development, innate immunity, and tumors [9 ]
.
In this study, it was found that NONO is a new TAZ-specific interacting protein, while the other two paraspeckle proteins (PSF/SFPQ, PSPC1) do not interact with TAZ
.
Studies have also shown that NONO can mediate the transcriptional activation of TAZ LLPS and TAZ/Tead in the nucleus; at the same time, the interaction between TAZ/NONO and TAZ/TEAD regulates TAZ-mediated target genes CTGF and CYR61 in different time and space.
Expression
.
Knockout of NONO significantly reduces nuclear TAZ LLPS, while overexpression of NONO promotes TAZ’s LLPS; at the same time knocking out NONO also significantly reduces the interaction of TAZ with TEAD, Rpb1 (the main component of RNA Pol II) and enhancers (Picture 1)
.
In addition, the study found that the degree of tumor malignancy was positively correlated with the high expression of NONO by examining the specimens of glioma patients, and the high expression of NONO and TAZ significantly shortened the prognostic survival of GBM patients
.
In the orthotopic glioblastoma mouse model, reducing NONO expression significantly inhibited TAZ-driven tumorigenesis and prolonged the survival time of mice
.
Therefore, this study shows that NONO, as an intranuclear factor, promotes the oncogenic transcriptional program driven by TAZ LLPS and TAZ
.
These findings provide potential drug targets for keratoblastoma and have important clinical significance for the treatment of this tumor
.
The results of the study were published in the journal Advanced Science in October 2021
.
Associate Professor Wei Li of the Hershey Medical Research Center of Pennsylvania State University is the corresponding author of the study.
Assistant Professor Wei Yiju of his research group and Assistant Professor Luo Huacheng of Professor Suming Huang's research group are the co-first authors of the research
.
WILEY paper information: The paraspeckle protein NONO promotes TAZ phase separation in the nucleus to drive glioblastoma oncogenic transcriptional program.
Yiju Wei#, Huacheng Luo#, Patricia Yee, Lijun Zhang, Zhijun Liu, Haiyan Zheng, Lei Zhang, Benjamin Anderson, Miaolu Tang , Suming Huang, and Wei Li*.
Advanced Science DOI: 10.
1002/advs.
202102653 Click "Read the original text" in the lower left corner to view the original text of the paper
.
Introduction to AdvancedScience Journal "Advanced Science" (Advanced Science) Wiley is a high-quality open source journal founded in 2014.
It publishes innovative achievements and cutting-edge progress in various fields such as materials science, physical chemistry, biomedicine, and engineering
.
The journal is dedicated to disseminating scientific research results to the public to the greatest extent, and all articles are freely available
.
The latest impact factor is 16.
806, and the 2020 SCI journals of the Chinese Academy of Sciences will be divided into the Q1 area of the material science category and the Q1 area of the engineering technology category
.
Press and hold the QR code on the official WeChat platform of AdvancedScienceNewsWiley's scientific research information.
Follow us to share cutting-edge information｜Focus on scientific research trends to publish scientific research news or apply for information sharing, please contact: ASNChina@Wiley.
com
