Paraspeckle Protein NONO Promotes TAZ Phase Separation in the Nucleus to Drive the Oncogenic Transcriptional Program

Wei, Yiju; Luo, Huacheng; Yee, Patricia; Zhang, Lijun; Liu, Zhijun; Zheng, Haiyan; Zhang, Lei; Anderson, Benjamin M.; Tang, Miaolu; Huang, Suming; Li, Wei

doi:10.1002/advs.202102653

Cited by 38 publications

(25 citation statements)

References 47 publications

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“…Whilst a role for NONO-driven phase separation in paraspeckle formation is yet to be established, NONO phase separation is required for radiation-induced DNA damage repair (Fan et al, 2021). In addition, NONO also promotes phase separation and activation of TAZ, the hippo pathway effector, to drive oncogenic transcription and tumorigenesis in glioblastoma, although a direct role for phase separation of NONO itself was not addressed in that study (Wei, Luo et al, 2021). Thus, NONO phase separation may be important for many of its regulatory activities in different contexts.…”

Section: Discussionmentioning

confidence: 99%

RNA binding is essential for NONO condensates to modulate pre-mRNA processing of super enhancer-associated genes in neuroblastoma

Zhang

Cooper

Chong

et al. 2022

Preprint

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High-risk neuroblastoma patients have poor survival rates and require better therapeutic options. High expression of a multifunctional DNA and RNA binding protein, NONO, in neuroblastoma is associated with poor patient outcome, however there is little understanding of the mechanism of NONO-dependent oncogenic gene regulatory activity in neuroblastoma. Here, we used cell imaging, biophysical and molecular analysis to reveal complex NONO-dependent regulation of gene expression, finding that NONO forms RNA- and DNA-tethered phase-separated condensates throughout the nucleus. CLIP analyses show that NONO mainly binds to the 5' end of pre-mRNAs and modulates pre-mRNA processing, dependent on its RNA binding activity. NONO preferentially regulates super enhancer-associated genes, including HAND2 and GATA2. In the absence of functional NONO-RNA condensates, inefficient pre-mRNA processing at these loci leads to decreased expression of HAND2 and GATA2. Thus, future development of agents that target RNA binding activity of NONO may have therapeutic potential in this cancer context.

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Section: Discussionmentioning

confidence: 99%

RNA binding is essential for NONO condensates to modulate pre-mRNA processing of super enhancer-associated genes in neuroblastoma

Zhang

Cooper

Chong

et al. 2022

Preprint

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“…Overexpression of NONO promoted nuclear TAZ phase separation, while low expression of NONO decreased nuclear TAZ phase separation. Moreover, the low expression of NONO inhibited the interaction of TAZ with enhancers and TEAD [147]. In addition, the phase separation of LATS1 can be promoted by phosphatidic acid-binding lncRNA SNHG9, thereby promoting carcinogenic YAP signaling.…”

Section: Llps In Hippo Signalingmentioning

confidence: 99%

Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

Qiu¹,

Tan²,

Xia³

et al. 2022

Int. J. Biol. Sci.

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Cancer is a public health problem of great concern, and it is also one of the main causes of death in the world. Cancer is a disease characterized by dysregulation of diverse cellular processes, including avoiding growth inhibitory factors, avoiding immune damage and promoting metastasis, etc. However, the precise mechanism of tumorigenesis and tumor progression still needs to be further elucidated. Formations of liquid-liquid phase separation (LLPS) condensates are a common strategy for cells to achieve diverse functions, such as chromatin organization, signal transduction, DNA repair and transcriptional regulation, etc. The biomolecular aggregates formed by LLPS are mainly driven by multivalent weak interactions mediated by intrinsic disordered regions (IDRs) in proteins. In recent years, aberrant phase separations and transition have been reported to be related to the process of various diseases, such as neurodegenerative diseases and cancer. Herein, we discussed recent findings that phase separation regulates tumor-related signaling pathways and thus contributes to tumor progression. We also reviewed some tumor virus-associated proteins to regulate the development of virus-associated tumors via phase separation. Finally, we discussed some possible strategies for treating tumors by targeting phase separation.

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“…NONO, an RNA/DNA binding protein, drives oncogenic transcriptional programs to promote tumorigenesis. 33 NONO interacts with the hypoxia inducible factor-1/2 complex and its downstream transcripts to activate the transcription of hypoxia-induced genes, which facilitate HCC progression. 34 CENPI, a member of the centromere protein family, has an essential role in accurate chromosome segregation.…”

Section: Dovepressmentioning

confidence: 99%

CSTF2 Acts as a Prognostic Marker Correlated with Immune Infiltration in Hepatocellular Carcinoma

Zhang¹,

Wan²,

Zhang³

et al. 2022

CMAR

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Background: Cleavage stimulation factor 2 (CSTF2) encodes a nuclear protein that is implicated in the development of various cancers. However, the role of CSTF2 in hepatocellular carcinoma (HCC) has not been understood. This study aims to explore the function of CSTF2 in HCC. Methods: The expression, diagnostic capability, prognostic value, and immune cell effect of CSTF2 in HCC were explored using various databases. The expression level of CSTF2 were validated in our cell lines. The effect of CSTF2 on hepatocarcinogenesis was explored by CSTF2 silencing. Results: CSTF2 expression was significantly elevated in HCC and correlated with multiple clinicopathological characteristics. CSTF2 exhibited good diagnostic capability in discriminating HCC samples from nontumorous samples. High CSTF2 expression was significantly related to poor overall survival. Univariate and multivariate Cox regression analyses suggested that CSTF2 expression was an independent risk factor for HCC. These results were validated in ICGC cohorts. In addition, the nomogram based on CSTF2 showed better predictive performance than the AJCC staging system in TCGA and ICGC cohorts. Functional enrichment analysis revealed that CSTF2-related genes were involved in DNA/RNA processing and the cell cycle. In addition, we found that CSTF2 expression was closely related to the levels of various infiltrating immune cells, especially neutrophils. Moreover, some immune checkpoints had positive relationships with CSTF2 expression. CSTF2 silencing inhibited proliferation, invasion and migration, and promoted apoptosis in HepG2 cells. Western blotting analysis revealed that CSTF2 silencing inactivated the Wnt/β-catenin signaling pathway. Conclusion: High CSTF2 expression not only correlates with unfavorable outcomes but also affects immune cell infiltration and immune checkpoint expression in HCC. CSTF2 silencing can alleviate the malignant phenotypes of hepatic cancer cell by inactivating the Wnt/β-catenin signaling pathway. These results indicate that CSTF2 can serve as a promising prognostic marker and therapeutic target for HCC patients.

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Paraspeckle Protein NONO Promotes TAZ Phase Separation in the Nucleus to Drive the Oncogenic Transcriptional Program

Cited by 38 publications

References 47 publications

RNA binding is essential for NONO condensates to modulate pre-mRNA processing of super enhancer-associated genes in neuroblastoma

RNA binding is essential for NONO condensates to modulate pre-mRNA processing of super enhancer-associated genes in neuroblastoma

Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

CSTF2 Acts as a Prognostic Marker Correlated with Immune Infiltration in Hepatocellular Carcinoma

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