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Article ; Online: The pleiotropic nature of NONO, a master regulator of essential biological pathways in cancers.

Ronchetti, Domenica / Traini, Valentina / Silvestris, Ilaria / Fabbiano, Giuseppina / Passamonti, Francesco / Bolli, Niccolò / Taiana, Elisa

Cancer gene therapy

2024

Abstract: NONO is a member of the Drosophila behavior/human splicing (DBHS) family of proteins. NONO is a multifunctional protein that acts as a "molecular scaffold" to carry out versatile biological activities in many aspects of gene regulation, cell ... ...

Abstract	NONO is a member of the Drosophila behavior/human splicing (DBHS) family of proteins. NONO is a multifunctional protein that acts as a "molecular scaffold" to carry out versatile biological activities in many aspects of gene regulation, cell proliferation, apoptosis, migration, DNA damage repair, and maintaining cellular circadian rhythm coupled to the cell cycle. Besides these physiological activities, emerging evidence strongly indicates that NONO-altered expression levels promote tumorigenesis. In addition, NONO can undergo various post-transcriptional or post-translational modifications, including alternative splicing, phosphorylation, methylation, and acetylation, whose impact on cancer remains largely to be elucidated. Overall, altered NONO expression and/or activities are a common feature in cancer. This review provides an integrated scenario of the current understanding of the molecular mechanisms and the biological processes affected by NONO in different tumor contexts, suggesting that a better elucidation of the pleiotropic functions of NONO in physiology and tumorigenesis will make it a potential therapeutic target in cancer. In this respect, due to the complex landscape of NONO activities and interactions, we highlight caveats that must be considered during experimental planning and data interpretation of NONO studies.
Language	English
Publishing date	2024-03-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1212513-1
ISSN	1476-5500 ; 0929-1903
ISSN (online)	1476-5500
ISSN	0929-1903
DOI	10.1038/s41417-024-00763-x
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Article ; Online: Bioinformatics Pipeline to Analyze lncRNA Arrays.

Todoerti, Katia / Ronchetti, Domenica / Manzoni, Martina / Taiana, Elisa / Neri, Antonino / Agnelli, Luca

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2348, Page(s) 45–53

Abstract: Despite the fact that next-generation sequencing approaches, in particular RNA sequencing, provide deep genome-wide expression data that allow both careful annotations/mapping of long noncoding RNA (lncRNA) molecules and de-novo sequencing, lncRNA ... ...

Abstract	Despite the fact that next-generation sequencing approaches, in particular RNA sequencing, provide deep genome-wide expression data that allow both careful annotations/mapping of long noncoding RNA (lncRNA) molecules and de-novo sequencing, lncRNA expression studies by microarray is a still cost-effective procedure that could allow to have a landscape of the most characterized lncRNA species. However, microarray design does not always correctly address the overlap between coding and noncoding samples to discriminate between the original transcript source. In order to overcome this issue, in this chapter we present a bioinformatics pipeline that enables accurate annotation of GeneChip
MeSH term(s)	Algorithms ; Computational Biology/methods ; Databases, Genetic ; Gene Expression Profiling/methods ; Genome-Wide Association Study/methods ; Humans ; Molecular Sequence Annotation ; Oligonucleotide Array Sequence Analysis/methods ; RNA, Long Noncoding ; Software ; Transcriptome ; User-Computer Interface
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2021-06-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1581-2_3
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Article ; Online: Expression levels of NONO, a nuclear protein primarily involved in paraspeckles function, are associated with several deregulated molecular pathways and poor clinical outcome in multiple myeloma.

Ronchetti, Domenica / Favasuli, Vanessa Katia / Silvestris, Ilaria / Todoerti, Katia / Torricelli, Federica / Bolli, Niccolò / Ciarrocchi, Alessia / Taiana, Elisa / Neri, Antonino

Discover. Oncology

2022 Volume 13, Issue 1, Page(s) 124

Abstract: Purpose: The NONO protein belongs to the multifunctional family of proteins that can bind DNA, RNA and proteins. It is located in the nucleus of most mammalian cells and can affect almost every step of gene regulation. Dysregulation of NONO has been ... ...

Abstract	Purpose: The NONO protein belongs to the multifunctional family of proteins that can bind DNA, RNA and proteins. It is located in the nucleus of most mammalian cells and can affect almost every step of gene regulation. Dysregulation of NONO has been found in many types of cancer; however, data regarding its expression and relevance in Multiple Myeloma (MM) are virtually absent. Methods: We took advantage of a large cohort of MM patients enrolled in the Multiple Myeloma Research Foundation CoMMpass study to elucidate better the clinical and biological relevance of NONO expression in the context of the MM genomic landscape and transcriptome. Results: NONO is overexpressed in pathological samples compared to normal controls. In addition, higher NONO expression levels are significant independent prognostic markers of worse clinical outcome in MM. Our results indicate that NONO deregulation may play a pathogenetic role in MM by affecting cell cycle, DNA repair mechanisms, and influencing translation by regulating ribosome biogenesis and assembly. Furthermore, our data suggest NONO involvement in the metabolic reprogramming of glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the 'Warburg Effect' that supports rapid cancer cell growth, survival, and invasion. Conclusion: These findings strongly support the need of future investigations for the understanding of the mechanisms of deregulation and the biological role and activity of NONO in MM.
Language	English
Publishing date	2022-11-11
Publishing country	United States
Document type	Journal Article
ISSN	2730-6011
ISSN (online)	2730-6011
DOI	10.1007/s12672-022-00582-2
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Article ; Online: Molecular Modelling of NONO and SFPQ Dimerization Process and RNA Recognition Mechanism.

Laurenzi, Tommaso / Palazzolo, Luca / Taiana, Elisa / Saporiti, Simona / Ben Mariem, Omar / Guerrini, Uliano / Neri, Antonino / Eberini, Ivano

International journal of molecular sciences

2022 Volume 23, Issue 14

Abstract: NONO and SFPQ are involved in multiple nuclear processes (e.g., pre-mRNA splicing, DNA repair, and transcriptional regulation). These proteins, along with NEAT1, enable paraspeckle formation, thus promoting multiple myeloma cell survival. In this paper, ... ...

Abstract	NONO and SFPQ are involved in multiple nuclear processes (e.g., pre-mRNA splicing, DNA repair, and transcriptional regulation). These proteins, along with NEAT1, enable paraspeckle formation, thus promoting multiple myeloma cell survival. In this paper, we investigate NONO and SFPQ dimer stability, highlighting the hetero- and homodimer structural differences, and model their interactions with RNA, simulating their binding to a polyG probe mimicking NEAT1guanine-rich regions. We demonstrated in silico that NONO::SFPQ heterodimerization is a more favorable process than homodimer formation. We also show that NONO and SFPQ RRM2 subunits are primarily required for protein-protein interactions with the other DBHS protomer. Simulation of RNA binding to NONO and SFPQ, beside validating RRM1 RNP signature importance, highlighted the role of β2 and β4 strand residues for RNA specific recognition. Moreover, we demonstrated the role of the NOPS region and other protomer's RRM2 β2/β3 loop in strengthening the interaction with RNA. Our results, having deepened RNA and DBHS dimer interactions, could contribute to the design of small molecules to modulate the activity of these proteins. RNA-mimetics, able to selectively bind to NONO and/or SFPQ RNA-recognition site, could impair paraspeckle formation, thus representing a first step towards the discovery of drugs for multiple myeloma treatment.
MeSH term(s)	DNA-Binding Proteins/metabolism ; Dimerization ; Humans ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; PTB-Associated Splicing Factor/metabolism ; Protein Subunits/metabolism ; RNA/metabolism ; RNA Splicing Factors/metabolism ; RNA-Binding Proteins/metabolism
Chemical Substances	DNA-Binding Proteins ; NONO protein, human ; PTB-Associated Splicing Factor ; Protein Subunits ; RNA Splicing Factors ; RNA-Binding Proteins ; RNA (63231-63-0)
Language	English
Publishing date	2022-07-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23147626
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Article ; Online: DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome.

Todoerti, Katia / Ronchetti, Domenica / Favasuli, Vanessa / Maura, Francesco / Morabito, Fortunato / Bolli, Niccolò / Taiana, Elisa / Neri, Antonino

Haematologica

2022 Volume 107, Issue 4, Page(s) 921–932

Abstract: DIS3 gene mutations occur in roughly 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), which occur in approximately 40% of MM cases. Despite several reports on the prevalence of DIS3 ... ...

Abstract	DIS3 gene mutations occur in roughly 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), which occur in approximately 40% of MM cases. Despite several reports on the prevalence of DIS3 mutations, their contribution to the pathobiology of MM remains largely unknown. We took advantage of the large public CoMMpass dataset to investigate the spectrum of DIS3 mutations in MM and its impact on the transcriptome and clinical outcome. We found that the clinical relevance of DIS3 mutations strictly depended on the co-occurrence of del(13q). In particular, bi-allelic DIS3 lesions significantly affected progression-free survival, independently of other predictors of poor clinical outcome, while mono-allelic events mostly affected overall survival. As expected, DIS3 mutations affect the MM transcriptome involving cellular processes and signaling pathways associated with RNA metabolism, and the deregulation of a large number of long non-coding RNA, among which we identified five distinct transcripts as independent predictors of poorer overall survival and nine of worse progression-free survival, with two (AC015982.2 and AL445228.3) predicting both unfavorable outcomes. These findings strongly prompt further studies investigating the relevance of these long non-coding RNA in MM.
MeSH term(s)	Exosome Multienzyme Ribonuclease Complex/genetics ; Exosome Multienzyme Ribonuclease Complex/metabolism ; Humans ; Multiple Myeloma/genetics ; Mutation ; RNA, Long Noncoding ; Transcriptome
Chemical Substances	RNA, Long Noncoding ; Exosome Multienzyme Ribonuclease Complex (EC 3.1.-) ; DIS3 protein, human (EC 3.1.13.-)
Language	English
Publishing date	2022-04-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2021.278342
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Article ; Online: DIS3

Haematologica

2024 Volume 109, Issue 1, Page(s) 231–244

Abstract: DIS3 gene mutations occur in approximately 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), found in roughly 40% of MM cases. Despite the high incidence of DIS3 mutations and deletions, ...

Abstract	DIS3 gene mutations occur in approximately 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), found in roughly 40% of MM cases. Despite the high incidence of DIS3 mutations and deletions, the biological significance of DIS3 and its contribution to MM pathogenesis remain poorly understood. In this study we investigated the functional role of DIS3 in MM, by exploiting a loss-of-function approach in human MM cell lines. We found that DIS3 knockdown inhibits proliferation in MM cell lines and largely affects cell cycle progression of MM plasma cells, ultimately inducing a significant increase in the percentage of cells in the G0/G1 phase and a decrease in the S and G2/M phases. DIS3 plays an important role not only in the control of the MM plasma cell cycle, but also in the centrosome duplication cycle, which are strictly co-regulated in physiological conditions in the G1 phase. Indeed, DIS3 silencing leads to the formation of supernumerary centrosomes accompanied by the assembly of multipolar spindles during mitosis. In MM, centrosome amplification is present in about a third of patients and may represent a mechanism leading to genomic instability. These findings strongly prompt further studies investigating the relevance of DIS3 in the centrosome duplication process. Indeed, a combination of DIS3 defects and deficient spindle-assembly checkpoint can allow cells to progress through the cell cycle without proper chromosome segregation, generating aneuploid cells which ultimately lead to the development of MM.
MeSH term(s)	Humans ; Multiple Myeloma/pathology ; Centrosome/metabolism ; Centrosome/pathology ; Mitosis ; Cell Cycle/genetics ; Genomic Instability ; Exosome Multienzyme Ribonuclease Complex/metabolism
Chemical Substances	DIS3 protein, human (EC 3.1.13.-) ; Exosome Multienzyme Ribonuclease Complex (EC 3.1.-)
Language	English
Publishing date	2024-01-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.283274
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Article ; Online: LncRNA NEAT1 in Paraspeckles: A Structural Scaffold for Cellular DNA Damage Response Systems?

Taiana, Elisa / Ronchetti, Domenica / Todoerti, Katia / Nobili, Lucia / Tassone, Pierfrancesco / Amodio, Nicola / Neri, Antonino

Non-coding RNA

2020 Volume 6, Issue 3

Abstract: Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA (lncRNA) reported to be frequently deregulated in various types of cancers and neurodegenerative processes. NEAT1 is an indispensable structural component of paraspeckles (PSs), ... ...

Abstract	Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA (lncRNA) reported to be frequently deregulated in various types of cancers and neurodegenerative processes. NEAT1 is an indispensable structural component of paraspeckles (PSs), which are dynamic and membraneless nuclear bodies that affect different cellular functions, including stress response. Furthermore, increasing evidence supports the crucial role of NEAT1 and essential structural proteins of PSs (PSPs) in the regulation of the DNA damage repair (DDR) system. This review aims to provide an overview of the current knowledge on the involvement of NEAT1 and PSPs in DDR, which might strengthen the rationale underlying future NEAT1-based therapeutic options in tumor and neurodegenerative diseases.
Language	English
Publishing date	2020-07-01
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2813993-8
ISSN	2311-553X ; 2311-553X
ISSN (online)	2311-553X
ISSN	2311-553X
DOI	10.3390/ncrna6030026
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Article ; Online: Long non-coding RNAs in B-cell malignancies: a comprehensive overview.

Nobili, Lucia / Ronchetti, Domenica / Taiana, Elisa / Neri, Antonino

Oncotarget

2017 Volume 8, Issue 36, Page(s) 60605–60623

Abstract: B-cell malignancies constitute a large part of hematological neoplasias. They represent a heterogeneous group of diseases, including Hodgkin's lymphoma, most non-Hodgkin's lymphomas (NHL), some leukemias and myelomas. B-cell malignancies reflect defined ... ...

Abstract	B-cell malignancies constitute a large part of hematological neoplasias. They represent a heterogeneous group of diseases, including Hodgkin's lymphoma, most non-Hodgkin's lymphomas (NHL), some leukemias and myelomas. B-cell malignancies reflect defined stages of normal B-cell differentiation and this represents the major basis for their classification. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides, for which many recent studies have demonstrated a function in regulating gene expression, cell biology and carcinogenesis. Deregulated expression levels of lncRNAs have been observed in various types of cancers including hematological malignancies. The involvement of lncRNAs in cancer initiation and progression and their attractive features both as biomarker and for therapeutic research are becoming increasingly evident. In this review, we summarize the recent literature to highlight the status of the knowledge of lncRNAs role in normal B-cell development and in the pathogenesis of B-cell tumors.
Language	English
Publishing date	2017-09-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.17303
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Article: Dissecting the Biological Relevance and Clinical Impact of lncRNA MIAT in Multiple Myeloma.

Todoerti, Katia / Ronchetti, Domenica / Puccio, Noemi / Silvestris, Ilaria / Favasuli, Vanessa / Amodio, Nicola / Gentile, Massimo / Morabito, Fortunato / Neri, Antonino / Taiana, Elisa

Cancers

2021 Volume 13, Issue 21

Abstract: The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an essential aspect of the investigation, which may contribute to understanding the disease's complex pathobiology, providing novel potential therapeutic targets. ...

Abstract	The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an essential aspect of the investigation, which may contribute to understanding the disease's complex pathobiology, providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the clinical relevance of the lncRNA MIAT in MM, taking advantage of the publicly available CoMMpass database. MIAT expression in MM is highly heterogeneous and significantly associated with specific molecular lesions frequently occurring in MM. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of MIAT in different signaling pathways and ribosome biogenesis and assembly. These findings suggest that MIAT deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and, indirectly, the translational process. Although MIAT expression levels seem not to be significantly associated with clinical outcome in multivariate analyses, high MIAT expression levels are associated with bortezomib resistance, this suggesting that MIAT targeting could overcome drug resistance in MM. These findings strongly prompt for further studies investigating the significance of MIAT in MM.
Language	English
Publishing date	2021-11-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13215518
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Article: Genomic Instability in Multiple Myeloma: A "Non-Coding RNA" Perspective.

Taiana, Elisa / Gallo Cantafio, Maria Eugenia / Favasuli, Vanessa Katia / Bandini, Cecilia / Viglietto, Giuseppe / Piva, Roberto / Neri, Antonino / Amodio, Nicola

Cancers

2021 Volume 13, Issue 9

Abstract: Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal proliferation of malignant plasma cells (PCs) within a permissive bone marrow microenvironment. The pathogenesis of MM is unequivocally linked to the acquisition of ... ...

Abstract	Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal proliferation of malignant plasma cells (PCs) within a permissive bone marrow microenvironment. The pathogenesis of MM is unequivocally linked to the acquisition of genomic instability (GI), which indicates the tendency of tumor cells to accumulate a wide repertoire of genetic alterations. Such alterations can even be detected at the premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) and, overall, contribute to the acquisition of the malignant traits underlying disease progression. The molecular basis of GI remains unclear, with replication stress and deregulation of DNA damage repair pathways representing the most documented mechanisms. The discovery that non-coding RNA molecules are deeply dysregulated in MM and can target pivotal components of GI pathways has introduced a further layer of complexity to the GI scenario in this disease. In this review, we will summarize available information on the molecular determinants of GI in MM, focusing on the role of non-coding RNAs as novel means to tackle GI for therapeutic intervention.
Language	English
Publishing date	2021-04-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13092127
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