Marin-Bejar, O. (Oskar)
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- The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element(2017) Grossi, E. (Elena); Gonzalez-Rojas, S.J. (Sandra Jovanna); Guo, S. (Shuling); Martínez, D. (Dannys); Rouzaut, A. (Ana); Marin-Bejar, O. (Oskar); Athie-Cuervo, A. (Alejandro); Ulitsky, I. (Igor); Huarte-Martínez, M. (Maite); Raimondi, I. (Iván); Morales-Urteaga, X. (Xabier); Galduroz, M. (Mikel); Mas, A. (Aina)Background: It is now obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long non-coding RNAs (lncRNAs). Many lncRNAs show aberrant expression in cancer, and some of them have been linked to cell transformation. However, the underlying mechanisms remain poorly understood and it is unknown how the sequences of lncRNA dictate their function. Results: Here we characterize the function of the p53-regulated human lncRNA LINC-PINT in cancer. We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells. A cross-species analysis identifies a highly conserved sequence element in LINC-PINT that is essential for its function. This sequence mediates a specific interaction with PRC2, necessary for the LINC-PINT-dependent repression of a pro-invasion signature of genes regulated by the transcription factor EGR1. Conclusions: Our findings support a conserved functional co-dependence between LINC-PINT and PRC2 and lead us to propose a new mechanism where the lncRNA regulates the availability of free PRC2 at the proximity of co-regulated genomic loci.
- Analysis of copy number alterations reveals the lncRNA ALAL-1 as a regulator of lung cancer immune evasion(Rockefeller University Pres, 2020) Pajares, M.J. (María José); Gonzalez-Rojas, S.J. (Sandra Jovanna); Kanduri, C. (Chandrasekhar); Martínez, D. (Dannys); Lozano-Moreda, T. (Teresa); Kumar-Juvvuna, P. (Prasanna); Marin-Bejar, O. (Oskar); Athie-Cuervo, A. (Alejandro); Montuenga-Badia, L.M. (Luis M.); Huarte-Martínez, M. (Maite); Raimondi, I. (Iván); Abad, A. (Amaya); Marchese, F.P. (Francesco P.); Ajona, D. (Daniel); Serizay, J. (Jacques); Sandoval, J. (Juan); Lasarte, J.J. (Juan José)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 lncRNA 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 TNFα− and NF-κB–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.
- Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia(Ferrata Storti Foundation, 2011) Sierra, J. (Jorge); Cervera, J. (Jose); Marin-Bejar, O. (Oskar); Valencia, A. (Ana); Sanz, M.A. (Miguel A.); Lahortiga, I. (Idoya); Marcotegui, N. (Nerea); Gomez-Casares, M.T. (María T.); Gomez-Benito, M. (María); Vazquez, I. (Iria); Hernandez-Rivas, J.M. (Jesús M.); Lumbreras, E. (Eva); Brunet, S. (Salut); Carranza, C. (Claudia); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Maicas, M. (Miren); Aguirre-Ena, X. (Xabier); Vicente, C. (Carmen)BACKGROUND: The EVI1 gene (3q26) codes for a zinc finger transcription factor with important roles in both mammalian development and leukemogenesis. Over-expression of EVI1 through either 3q26 rearrangements, MLL fusions, or other unknown mechanisms confers a poor prognosis in acute myeloid leukemia. DESIGN AND METHODS: We analyzed the prevalence and prognostic impact of EVI1 over-expression in a series of 476 patients with acute myeloid leukemia, and investigated the epigenetic modifications of the EVI1 locus which could be involved in the transcriptional regulation of this gene. RESULTS: Our data provide further evidence that EVI1 over-expression is a poor prognostic marker in acute myeloid leukemia patients less than 65 years old. Moreover, we found that patients with no basal expression of EVI1 had a better prognosis than patients with expression/over-expression (P=0.036). We also showed that cell lines with over-expression of EVI1 had no DNA methylation in the promoter region of the EVI1 locus, and had marks of active histone modifications: H3 and H4 acetylation, and trimethylation of histone H3 lysine 4. Conversely, cell lines with no expression of EVI1 have DNA hypermethylation and are marked by repressive trimethylation of histone H3 lysine 27 at the EVI1 promoter. CONCLUSIONS: Our results identify EVI1 over-expression as a poor prognostic marker in a large, independent cohort of acute myeloid leukemia patients less than 65 years old, and show that the total absence of EVI1 expression has a prognostic impact on the outcome of such patients. Furthermore, we demonstrated for the first time that an aberrant epigenetic pattern involving DNA methylation, H3 and H4 acetylation, and trimethylation of histone H3 lysine 4 and histone H3 lysine 27 might play a role in the transcriptional regulation of EVI1 in acute myeloid leukemia. This study opens new avenues for a better understanding of the regulation of EVI1 expression at a transcriptional level.
- Functional Characterization of p53: Induced Noncoding Transcript (Lincpint)(2015-05-26) Marin-Bejar, O. (Oskar); Huarte-Martínez, M. (Maite)The p53 transcription factor regulates a complex transcriptional network that is crucial to maintain cellular homeostasis. Only recently it has become clear that p53 regulates the expression of several long intergenic noncoding RNAs (lincRNAs). One of them, named Lincpint (p53 induced noncoding transcript), is the subject of this study. Lincpint is a direct transcriptional target of p53. In mouse cells, Lincpint promotes cell proliferation and survival by regulating the expression of genes of the TGF-β, MAPK and p53 pathways. Lincpint is a nuclear lincRNA that directly interacts with the Polycomb repressive complex 2 (PRC2), and is required for PRC2 targeting of specific genes for H3K27 tri-methylation and repression. Murine Lincpint has an ortholog in human (LINC-PINT), which presents suggestive analogies with the murine lincRNA, such as its regulation by p53. Its expression significantly correlates with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, LINC-PINT is downregulated multiple tumor types. Its overexpression inhibits the proliferation, in vivo tumor growth and migration-invasion capability of tumor cells. Altogether, these data suggest a possible role of LINC-PINT as tumor suppressor.