IncRNA y regulación del genoma de cáncer

Grupos Investigadores

Miembros del Grupo

Coordinador

Huarte Martínez, Maite

(maitehuarte@unav.es)

Investigadores

Aida

Arcas Mantas

Sandra Jovanna

González Rojas

Enrique

Goñi Echeverria

Igor

Ruiz de Los Mozos Aliaga

Luisa

Statello

Colaboradores

Daniel

Elvira Blazquez

Aina María

Mas Calafell

Líneas de Investigación

Desarrollo de nuevos métodos de cribado de alto rendimiento para el estudio funcional de IncRNAs en el cáncer.
Estudio de IncRNAs en la vía supresora tumoral de p53 y su relación con la senescencia celular.
Identificación de IncRNAs con papeles oncogénicos o supresores tumorales a través de herramientas genómicas.
Investigación del papel de los IncRNAs en la replicación de la cromatina e inestabilidad genómica.

Palabras Clave

CRISPRI/CRISPRa
Cáncer colorectal
Epigenética
Genómica funcional
LncRNA
p53
Regulación del genoma y el transcriptoma
Transcriptomica

Publicaciones Científicas desde 2018

Publicaciones en Revistas

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Libros

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Publicaciones en Revistas

Capítulos de Libros

Libros

Autores: Mattick, J. S. (Autor de correspondencia); Amaral, P. P.; Carninci, P.; et al.

Título: Long non-coding RNAs: definitions, functions, challenges and recommendations

Revista: NATURE REVIEWS MOLECULAR CELL BIOLOGY

ISSN: 1471-0072 Vol.24 2023 págs. 430 - 447

Resumen

Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term 'lncRNAs' encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.
Autores: Avalle, L. (Autor de correspondencia); Raggi, L.; Monteleone, E.; et al.

Título: STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts

Revista: ONCOGENE

ISSN: 0950-9232 Vol.41 N° 10 2022 págs. 1456 - 1467

Resumen

In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.
Autores: Hluchy, M.; Gajduskova, P.; Ruiz de Los Mozos Aliaga, Igor; et al.

Título: CDK11 regulates pre-mRNA splicing by phosphorylation ofSF3B1

Revista: NATURE

ISSN: 0028-0836 Vol.609 N° 7928 2022 págs. 829 - 834

Resumen

RNA splicing, the process of intron removal from pre-mRNA, is essential for the regulation of gene expression. It is controlled by the spliceosome, a megadalton RNA-protein complex that assembles de novo on each pre-mRNA intron through an ordered assembly of intermediate complexes(1,2). Spliceosome activation is a major control step that requires substantial protein and RNA rearrangements leading to a catalytically active complex(1-5). Splicing factor 3B subunit 1 (SF3B1) protein-a subunit of the U2 small nuclear ribonucleoprotein(6)-is phosphorylated during spliceosome activation(7-)(10), but the kinase that is responsible has not been identified. Here we show that cyclin-dependent kinase 11 (CDK11) associates with SF3B1 and phosphorylates threonine residues at its N terminus during spliceosome activation. The phosphorylation is important for the association between SF3B1 and U5 and U6 snRNAs in the activated spliceosome, termed the B(act )complex, and the phosphorylation can be blocked by OTS964, a potent and selective inhibitor of CDK11. Inhibition of CDK11 prevents spliceosomal transition from the precatalytic complex B to the activated complex B-act and leads to widespread intron retention and accumulation of non-functional spliceosomes on pre-mRNAs and chromatin. We demonstrate a central role of CDK11 in spliceosome assembly and splicing regulation and characterize OTS964 as a highly selective CDK11 inhibitor that suppresses spliceosome activation and splicing.
Autores: Statello, Luisa; Guo, C. J.; Chen, L. L.; et al.

Título: Gene regulation by long non-coding RNAs and its biological functions

Revista: NATURE REVIEWS MOLECULAR CELL BIOLOGY

ISSN: 1471-0072 Vol.22 N° 2 2021 págs. 96 - 118

Resumen

Recent studies have provided novel insight into the biogenesis of long non-coding RNAs (lncRNAs) and their specific functions. The functions of lncRNAs vary from transcriptional and post-transcriptional gene regulation to the assembly and function of membraneless nuclear bodies, and are relevant to neuronal disorders, immune responses and cancer. Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.
Autores: Mitra, S.; Muralidharan, S. V.; Di Marco, M.; et al.

Título: Subcellular distribution of p53 by the p53-responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma

Revista: CANCER RESEARCH

ISSN: 0008-5472 Vol.81 N° 6 2021 págs. 1457 - 1471

Resumen

Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wildtype p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for patients with high-risk neuroblastoma. Significance: This study shows how a p53-responsive lncRNA mediates chemotherapeutic response by modulating nuclear p53 pathways and identifies a potential treatment strategy for patients with high-risk neuroblastoma.
Autores: Mas, A. M.; Huarte Martínez, Maite (Autor de correspondencia)

Título: lncRNA-DNA hybrids regulate distant genes

Revista: EMBO REPORTS

ISSN: 1469-221X Vol.21 N° 3 2020

Resumen

lncRNAs actively regulate gene expression. They contribute to chromosomal interactions at close or distant genomic regions, which, in turn, regulate transcription [1]. Ariel et al [2] reveal in a recent study a new molecular mechanism of the Arabidopsis lncRNA APOLO. The authors extend previously reported functions of APOLO in cis-regulation of chromosomal looping and transcription of its neighbor gene to a set of distant genes involved in auxin-induced molecular pathways controlling lateral root development. Noteworthy, APOLO recognition of multiple trans-modulated targets occurs through a novel mechanism involving R-loop formation.
Autores: Castroviejo, N. ; Ocana, O. H.; Rago, L. ; et al.

Título: Reply to: Zebrafish prrx1a mutants have normal hearts

Revista: NATURE

ISSN: 0028-0836 Vol.585 N° 7826 2020 págs. E17 - E19
Autores: Athie, A. ; Marchese, Francesco Paolo; González Rojas, Sandra Jovanna; et al.

Título: Analysis of copy number alterations reveals the lncRNA ALAL-1 as a regulator of lung cancer immune evasion

Revista: JOURNAL OF CELL BIOLOGY

ISSN: 0021-9525 Vol.219 N° 9 2020

Resumen

Cancer is characterized by genomic instability leading to deletion or amplification of oncogenes or tumor suppressors. However, most of the altered regions are devoid of known cancer drivers. Here, we identify lncRNAs frequently lost or amplified in cancer. Among them, we found amplified IncRNA associated with lung cancer-1 (ALAL-1) as frequently amplified in lung adenocarcinomas. ALAL-1 is also overexpressed in additional tumor types, such as lung squamous carcinoma. The RNA product of ALAL-1 is able to promote the proliferation and tumorigenicity of lung cancer cells. ALAL-1 is a TNF alpha- and NF-kappa B-induced cytoplasmic lncRNA that specifically interacts with SART3, regulating the subcellular localization of the protein deubiquitinase USP4 and, in turn, its function in the cell. Interestingly, ALAL-1 expression inversely correlates with the immune infiltration of lung squamous tumors, while tumors with ALAL-1 amplification show lower infiltration of several types of immune cells. We have thus unveiled a pro-oncogenic lncRNA that mediates cancer immune evasion, pointing to a new target for immune potentiation.
Autores: Arcas Mantas, Aida; Wilkinson, D. G. ; Nieto, M. A. (Autor de correspondencia)

Título: The Evolutionary History of Ephs and Ephrins: Toward Multicellular Organisms

Revista: MOLECULAR BIOLOGY AND EVOLUTION

ISSN: 0737-4038 Vol.37 N° 2 2020 págs. 379 - 394

Resumen

Eph receptor (Eph) and ephrin signaling regulate fundamental developmental processes through both forward and reverse signaling triggered upon cell-cell contact. In vertebrates, they are both classified into classes A and B, and some representatives have been identified in many metazoan groups, where their expression and functions have been well studied. We have extended previous phylogenetic analyses and examined the presence of Eph and ephrins in the tree of life to determine their origin and evolution. We have found that 1) premetazoan choanoflagellates may already have rudimental Eph/ephrin signaling as they have an Eph-/ephrin-like pair and homologs of downstream-signaling genes; 2) both forward- and reverse-downstream signaling might already occur in Porifera since sponges have most genes involved in these types of signaling; 3) the nonvertebrate metazoan Eph is a type-B receptor that can bind ephrins regardless of their membrane-anchoring structure, glycosylphosphatidylinositol, or transmembrane; 4) Eph/ephrin cross-class binding is specific to Gnathostomata; and 5) kinase-dead Eph receptors can be traced back to Gnathostomata. We conclude that Eph/ephrin signaling is of older origin than previously believed. We also examined the presence of protein domains associated with functional characteristics and the appearance and conservation of downstream-signaling pathways to understand the original and derived functions of Ephs and ephrins. We find that the evolutionary history of these gene families points to an ancestral function in cell-cell interactions that could contribute to the emergence of multicellularity and, in particular, to the required segregation of cell populations.
Autores: Grossi, E. ; Raimondi, I. ; Goñi Echeverría, Enrique; et al.

Título: A IncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions

Revista: NATURE COMMUNICATIONS

ISSN: 2041-1723 Vol.11 N° 1 2020

Resumen

LncRNAs have been shown to be direct players in chromatin regulation, but little is known about their role at active genomic loci. We investigate the role of lncRNAs in gene activation by profiling the RNA interactome of SMARCB1-containing SWI/SNF complexes in proliferating and senescent conditions. The isolation of SMARCB1-associated transcripts, together with chromatin profiling, shows prevalent association to active regions where SMARCB1 differentially binds locally transcribed RNAs. We identify SWINGN, a IncRNA interacting with SMARCB1 exclusively in proliferating conditions, exerting a pro-oncogenic role in some tumor types. SWINGN is transcribed from an enhancer and modulates the activation of GAS6 oncogene as part of a topologically organized region, as well as a larger network of pro-oncogenic genes by favoring SMARCB1 binding. Our results indicate that SWINGN influences the ability of the SWI/SNF complexes to drive epigenetic activation of specific promoters, suggesting a SWI/SNF-RNA cooperation to achieve optimal transcriptional activation.
Autores: Saeinasab, M.; Bahrami, A. R.; González Rojas, Sandra Jovanna; et al.

Título: SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF (vol 38, 172, 2019)

Revista: JOURNAL OF EXPERIMENTAL AND CLINICAL CANCER RESEARCH

ISSN: 1756-9966 Vol.38 N° 1 2019 págs. 441

Resumen

In the original publication of this article,[1] the Funding section needs to be revised, and the corrected Funding section appears below.
Autores: Pazo, A.; Perez-Gonzalez, A.; Oliveros, J. C. ; et al.

Título: hCLE/RTRAF-HSPC117-DDX1-FAM98B: A New Cap-Binding Complex That Activates mRNA Translation

Revista: FRONTIERS IN PHYSIOLOGY

ISSN: 1664-042X Vol.10 N° 92 2019

Resumen

hCLE/C14orf166/RTRAF, DDX1, and HSPC117 are components of cytoplasmic mRNA-transporting granules kinesin-associated in dendrites. They have also been found in cytoplasmic ribosome-containing RNA granules that transport specific mRNAs halted for translation until specific neuronal signals renders them accessible to the translation machinery. hCLE associates to DDX1, HSPC117, and FAM98B in HEK293T cells and all four proteins bind to cap analog-containing resins. Competition and elution experiments indicate that binding of hCLE complex to cap resins is independent of elF4E; the cap-binding factor needed for translation. Purified hCLE free of its associated proteins binds cap with low affinity suggesting that its interacting proteins modulate its cap association. hCLE silencing reduces hCLE accumulation and that of its interacting proteins and decreases mRNA translation. hCLE-associated RNAs have been isolated and sequenced; RNAs involved in mRNA translation are specifically associated. The data suggest that RNA granules may co-transport RNAs encoding proteins involved in specific functions together with RNAs that encode proteins needed for the translation of these specific RNAs and indicate an important role for hCLE modulating mRNA translation.
Autores: Saeinasab, M.; Bahrami, A. R.; González Rojas, Sandra Jovanna; et al.

Título: SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF

Revista: JOURNAL OF EXPERIMENTAL AND CLINICAL CANCER RESEARCH

ISSN: 1756-9966 Vol.38 2019

Resumen

BackgroundThousands of long noncoding RNAs (lncRNAs) are aberrantly expressed in various types of cancers, however our understanding of their role in the disease is still very limited.MethodsWe applied RNAseq analysis from patient-derived data with validation in independent cohort of patients. We followed these studies with gene regulation analysis as well as experimental dissection of the role of the identified lncRNA by multiple in vitro and in vivo methods.ResultsWe analyzed RNA-seq data from tumors of 456 CRC patients compared to normal samples, and identified SNHG15 as a potentially oncogenic lncRNA that encodes a snoRNA in one of its introns. The processed SNHG15 is overexpressed in CRC tumors and its expression is highly correlated with poor survival of patients. Interestingly, SNHG15 is more highly expressed in tumors with high levels of MYC expression, while MYC protein binds to two E-box motifs on SNHG15 sequence, indicating that SNHG15 transcription is directly regulated by the oncogene MYC.The depletion of SNHG15 by siRNA or CRISPR-Cas9 inhibits cell proliferation and invasion, decreases colony formation as well as the tumorigenic capacity of CRC cells, whereas its overexpression leads to opposite effects. Gene expression analysis performed upon SNHG15 inhibition showed changes in multiple relevant genes implicated in cancer progression, including MYC, NRAS, BAG3 or ERBB3. Several of these genes are functionally related to AIF, a protein that we found to specifically interact with SNHG15, suggesting that the SNHG15 acts, at least in part, by regulating the activity of AIF. Interestingly, ROS levels, which are directly regulated by AIF, show a significant reduction in SNHG15-depleted cells. Moreover, knockdown of SNHG15 increases the sensitiveness of the cells to 5-FU, while its overexpression renders them more resistant to the chemotherapeutic drug.ConclusionAltogether, these results describe an important role of SNHG15 in promoting colon cancer and mediating drug resistance, suggesting its potential as prognostic marker and target for RNA-based therapies.
Autores: Grossi, Elena; Huarte Martínez, Maite (Autor de correspondencia)

Título: NON-CODING RNA A lncRNA GUARDINg genome integrity

Revista: NATURE CELL BIOLOGY

ISSN: 1465-7392 Vol.20 N° 4 2018 págs. 371 - 372
Autores: Marchese, Francesco Paolo; Huarte Martínez, Maite (Autor de correspondencia)

Título: A "Counter-Enhancer'' in Tumor Suppression

Revista: CELL

ISSN: 0092-8674 Vol.173 N° 6 2018 págs. 1318 - 1319

Resumen

The role of the noncoding genome in cancer biology is continually expanding. Cho et al. reveal a new and unexpected mechanism for the regulation of MYC expression mediated by the promoter sequence of its neighbor gene PVT1. This DNA element acts as a promoter-enhancer competitor and a candidate tumor suppressor.'
Autores: Mondal, T.; Juvvuna, P. K.; Kirkeby, A.; et al.

Título: Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Revista: CANCER CELL

ISSN: 1535-6108 Vol.33 N° 3 2018 págs. 417 - +

Resumen

Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
Autores: Torres-Bayona, S.; Aldaz, P.; Auzmendi-Iriarte, J.; et al.

Título: PR-LncRNA signature regulates glioma cell activity through expression of SOX factors

Revista: SCIENTIFIC REPORTS

ISSN: 2045-2322 Vol.8 N° 12746 2018

Resumen

Long non-coding RNAs (LncRNAs) have emerged as a relevant class of genome regulators involved in a broad range of biological processes and with important roles in tumor initiation and malignant progression. We have previously identified a p53-regulated tumor suppressor signature of LncRNAs (PR-LncRNAs) in colorectal cancer. Our aim was to identify the expression and function of this signature in gliomas. We found that the expression of the four PR-LncRNAs tested was high in human low-grade glioma samples and diminished with increasing grade of disease, being the lowest in glioblastoma samples. Functional assays demonstrated that PR-LncRNA silencing increased glioma cell proliferation and oncosphere formation. Mechanistically, we found an inverse correlation between PR-LncRNA expression and SOX1, SOX2 and SOX9 stem cell factors in human glioma biopsies and in glioma cells in vitro. Moreover, knock-down of SOX activity abolished the effect of PR-LncRNA silencing in glioma cell activity. In conclusion, our results demonstrate that the expression and function of PR-LncRNAs are significantly altered in gliomagenesis and that their activity is mediated by SOX factors. These results may provide important insights into the mechanisms responsible for glioblastoma pathogenesis.

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