Nuestros investigadores

Edurne San José Enériz

Publicaciones científicas más recientes (desde 2010)

Autores: Caruso, S. ; Llerena, S. ; Alvarez-Sola, G. ; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 69  Nº 2  2019  págs. 587 - 603
Epigenetic modifications such as DNA and histone methylation functionally cooperate in fostering tumor growth, including that of hepatocellular carcinoma (HCC). Pharmacological targeting of these mechanisms may open new therapeutic avenues. We aimed to determine the therapeutic efficacy and potential mechanism of action of our dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitor in human HCC cells and their crosstalk with fibrogenic cells. The expression of G9a and DNMT1, along with that of their molecular adaptor ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was measured in human HCCs (n = 268), peritumoral tissues (n = 154), and HCC cell lines (n = 32). We evaluated the effect of individual and combined inhibition of G9a and DNMT1 on HCC cell growth by pharmacological and genetic approaches. The activity of our lead compound, CM-272, was examined in HCC cells under normoxia and hypoxia, human hepatic stellate cells and LX2 cells, and xenograft tumors formed by HCC or combined HCC+LX2 cells. We found a significant and correlative overexpression of G9a, DNMT1, and UHRF1 in HCCs in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. CM-272 potently reduced HCC and LX2 cells proliferation and quelled tumor growth, particularly in HCC+LX2 xenografts. Mechanistically, CM-272 inhibited the metabolic adaptation of HCC cells to hypoxia and induced a differentiated phenotype in HCC and fibrogenic cells. The expression of the metabolic tumor suppressor gene fructose-1,6-bisphosphatase (FBP1), epigenetically repressed in HCC, was restored by CM-272. Conclusion: Combined targeting of G9a/DNMT1 with compounds such as CM-272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC.
Autores: Martínez, Nicolás; Pascual, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  Nº 8  2019  págs. 1572 - 1579
In this study we interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpG, corresponding to 10,253 genes, between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, most differentially methylated CpG were located outside gene promoter regions and showed significant association with enhancer regions. This aberrant enhancer hypermethylation was negatively correlated with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on the ZFP36L1 gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of patients and myeloid cell-lines. In vitro reporter assay and 5'-azacitidine treatment confirmed the functional relevance of hypermethylation of ZFP36L1 enhancer. Furthermore, in vitro rescue of ZFP36L1 expression had an impact on cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in myelofibrosis. Collectively, we describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing ZFP36L1 as a novel candidate tumor suppressor gene.
Autores: Segovia, C.; San José, Edurne; Munera-Maravilla, E.; et al.
Revista: NATURE MEDICINE
ISSN 1078-8956  Vol. 25  Nº 7  2019  págs. 1073 - 1081
Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances(1,2). Recent molecular characterization has defined new (epi) genetic drivers and potential targets for bladder cancer(3,4). The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients(5-8). Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten(loxP/loxP); Trp53(loxP/loxP); Rb1(loxP/loxP); Rbl1(-/-)) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
Autores: San José, Edurne; Gimenez-Camino, N.; Rabal, O. ; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 242 - 242
Autores: San José, Edurne; Garate, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  2019  págs. 49 - 49
Autores: Apaolaza, Iñigo; San José, Edurne; Agirre, X; et al.
Revista: MOLECULAR AND CELLULAR ONCOLOGY
ISSN 2372-3556  Vol. 30  Nº 5  2018  págs. e1389672.
The identification of therapeutic strategies exploiting the metabolic alterations of malignant cells is a relevant area in cancer research. Here, we discuss a novel computational method, based on the COBRA (COnstraint-Based Reconstruction and Analysis) framework for metabolic networks, to perform this task. Current and future steps are presented.
Autores: Sánchez-Arias; San José, Edurne; Agirre, X; et al.
Revista: JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0022-2623  Vol. 61  Nº 15  2018  págs. 6546-6573
Epigenetic regulators that exhibit aberrant enzymatic activities or expression profiles are potential therapeutic targets for cancers. Specifically, enzymes responsible for methylation at histone-3 lysine-9 (like G9a) and aberrant DNA hypermethylation (DNMTs) have been implicated in a number of cancers. Recently, molecules bearing a 4-aminoquinoline scaffold were reported as dual inhibitors of these targets and showed a significant in vivo efficacy in animal models of hematological malignancies. Here, we report a detailed exploration around three growing vectors born by this chemotype. Exploring this chemical space led to the identification of features to navigate G9a and DNMT1 biological spaces: not only their corresponding exclusive areas, selective compounds, but also common spaces. Thus, we identified from selective G9a and first-in-class DNMT1 inhibitors, >1 log unit between their IC50 values, with IC50 < 25 nM (e.g., 43 and 26, respectively) to equipotent inhibitors with IC50 < 50 nM for both targets (e.g., 13). Their ADME/Tox profiling and antiproliferative efficacies, versus some cancer cell lines, are also reported.
Autores: San José, Edurne; Ezponda, Teresa; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 9  Nº 16  2018  págs. 12842 - 12852
Long Non-Coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. Several lncRNAs are involved in cell proliferation and are deregulated in several human tumors. Few lncRNAs have been described to play a role in Acute Lymphoblastic Leukemia (ALL). In this study, we carried out a genome wide lncRNA expression profiling in ALL samples and peripheral blood samples obtained from healthy donors. We detected 43 lncRNAs that were aberrantly expressed in ALL. Interestingly, among them, linc-PINT showed a significant downregulation in T and B-ALL. Re-expression of linc-PINT in ALL cells induced inhibition of leukemic cell growth that was associated with apoptosis induction and cell cycle arrest in G2/M phase. linc-PINT induced the transcription of HMOX1 which reduced the viability of ALL cells. Intriguingly, we observed that treatment with anti-tumoral epigenetic drugs like LBH-589 (Panobinostat) and Curcumin induced the expression of linc-PINT and HMOX1 in ALL. These results indicate that the downregulation of linc-PINT plays a relevant role in the pathogenesis of ALL, and linc-PINT re-expression may be one of the mechanisms exerted by epigenetic drugs to reduce cell proliferation in ALL.
Autores: San José, Edurne; Agirre, X; Sánchez-Arias, JA; et al.
Revista: JOURNAL OF MEDICINAL CHEMISTRY
ISSN 0022-2623  Vol. 61  Nº 15  2018  págs. 6518-6545
Using knowledge- and structure-based approaches, we designed and synthesized reversible chemical probes that simultaneously inhibit the activity of two epigenetic targets, histone 3 lysine 9 methyltransferase (G9a) and DNA methyltransferases (DNMT), at nanomolar ranges. Enzymatic competition assays confirmed our design strategy: substrate competitive inhibitors. Next, an initial exploration around our hit 11 was pursued to identify an adequate tool compound for in vivo testing. In vitro treatment of different hematological neoplasia cell lines led to the identification of molecules with clear antiproliferative efficacies (GI50 values in the nanomolar range). On the basis of epigenetic functional cellular responses (levels of lysine 9 methylation and 5-methylcytosine), an acceptable therapeutic window (around 1 log unit) and a suitable pharmacokinetic profile, 12 was selected for in vivo proof-of-concept ( Nat. Commun. 2017 , 8 , 15424 ). Herein, 12 achieved a significant in vivo efficacy: 70% overall tumor growth inhibition of a human acute myeloid leukemia (AML) xenograft in a mouse model.
Autores: San José, Edurne; Agirre, X; Oyarzabal, Julen; et al.
Revista: MOLECULAR AND CELLULAR ONCOLOGY
ISSN 2372-3556  Vol. 4  Nº 4  2017 
Autores: Apaolaza, Iñigo; San José, Edurne; et al.
Revista: NATURE COMMUNICATIONS
ISSN 2041-1723  Vol. 8  Nº 1  2017  págs. 459
Synthetic lethality is a promising concept in cancer research, potentially opening new possibilities for the development of more effective and selective treatments. Here, we present a computational method to predict and exploit synthetic lethality in cancer metabolism. Our approach relies on the concept of genetic minimal cut sets and gene expression data, demonstrating a superior performance to previous approaches predicting metabolic vulnerabilities in cancer. Our genetic minimal cut set computational framework is applied to evaluate the lethality of ribonucleotide reductase catalytic subunit M1 (RRM1) inhibition in multiple myeloma. We present a computational and experimental study of the effect of RRM1 inhibition in four multiple myeloma cell lines. In addition, using publicly available genome-scale loss-of-function screens, a possible mechanism by which the inhibition of RRM1 is effective in cancer is established. Overall, our approach shows promising results and lays the foundation to build a novel family of algorithms to target metabolism in cancer.
Autores: San José, Edurne; Ochoa, María del Carmen; et al.
Revista: SCIENTIFIC REPORTS
ISSN 2045-2322  Vol. 7  2017 
Constraint-based modeling for genome-scale metabolic networks has emerged in the last years as a promising approach to elucidate drug targets in cancer. Beyond the canonical biosynthetic routes to produce biomass, it is of key importance to focus on metabolic routes that sustain the proliferative capacity through the regulation of other biological means in order to improve in-silico gene essentiality analyses. Polyamines are polycations with central roles in cancer cell proliferation, through the regulation of transcription and translation among other things, but are typically neglected in in silico cancer metabolic models. In this study, we analysed essential genes for the biosynthesis of polyamines. Our analysis corroborates the importance of previously known regulators of the pathway, such as Adenosylmethionine Decarboxylase 1 (AMD1) and uncovers novel enzymes predicted to be relevant for polyamine homeostasis. We focused on Adenine Phosphoribosyltransferase (APRT) and demonstrated the detrimental consequence of APRT gene silencing on different leukaemia cell lines. Our results highlight the importance of revisiting the metabolic models used for in-silico gene essentiality analyses in order to maximize the potential for drug target identification in cancer.
Autores: Rodriguez-Madoz, Juan Roberto, (Autor de correspondencia); San José, Edurne; Zapata, Natalia María; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 12  Nº 12  2017  págs. e0190275
The combination of defined factors with small molecules targeting epigenetic factors is a strategy that has been shown to enhance optimal derivation of iPSCs and could be used for disease modelling, high throughput screenings and/or regenerative medicine applications. In this study, we showed that a new first-in-class reversible dual G9a/DNMT1 inhibitor compound (CM272) improves the efficiency of human cell reprogramming and iPSC generation from primary cells of healthy donors and patient samples, using both integrative and non-integrative methods. Moreover, CM272 facilitates the generation of human iPSC with only two factors allowing the removal of the most potent oncogenic factor cMYC. Furthermore, we demonstrated that mechanistically, treatment with CM272 induces heterochromatin relaxation, facilitates the engagement of OCT4 and SOX2 transcription factors to OSKM refractory binding regions that are required for iPSC establishment, and enhances mesenchymal to epithelial transition during the early phase of cell reprogramming. Thus, the use of this new G9a/DNMT reversible dual inhibitor compound may represent an interesting alternative for improving cell reprogramming and human iPSC derivation for many different applications while providing interesting insights into reprogramming mechanism
Autores: San José, Edurne; Agirre, X; et al.
Revista: NATURE COMMUNICATIONS
ISSN 2041-1723  Vol. 8  2017  págs. 15424
The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.
Autores: Martínez, Nicolás; Pascual, M.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 130  Nº Supl. 1  2017 
Autores: Agirre, X; Castellano, G.; Pascual, M.; et al.
Revista: GENOME RESEARCH
ISSN 1088-9051  Vol. 25  Nº 4  2015  págs. 478 - 487
While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.
Autores: Agirre, X; Castellano, G.; Heath, S.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl. 4  2015  págs. 41 - 42
Autores: San José, Edurne; Agirre, X; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  2015  págs. 27
Autores: San José, Edurne; Agirre, X; Rabal, O.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 100  Nº Supl. 4  2015  págs. 60 - 61
Autores: Agirre, X; Castellano, G.; Health, S.; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 21  2014 
Autores: San José, Edurne; Agirre, X; Roa, Sergio; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 124  Nº 21  2014 
Autores: San José, Edurne; Agirre, X; Rodriguez, Paula; et al.
Revista: EPIGENOMICS
ISSN 1750-1911  Vol. 5  Nº 5  2013  págs. 525 - 538
Acute lymphoblastic leukemia (ALL) is a heterogeneous cancer that is characterized by rapid and uncontrolled proliferation of immature B- or T-lymphoid precursors. Although ALL has been regarded as a genetic disease for many years, the crucial importance of epigenetic alterations in leukemogenesis has become increasingly evident. Epigenetic mechanisms, which include DNA methylation and histone modifications, are critical for gene regulation during many key biological processes. Here, we review the cell signaling pathways that are regulated by DNA methylation or histone modifications in ALL. Recent studies have highlighted the fundamental role of these modifications in ALL development, and suggested that future investigation into the specific genes and pathways that are altered by epigenetic mechanisms can contribute to the development of novel drug-based therapies for ALL.
Autores: Rio, P.; Agirre, X; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 119  Nº 13  2012  págs. 3042 - 3049
Fanconi anemia (FA) is an inherited genetic disorder associated with BM failure and cancer predisposition. In the present study, we sought to elucidate the role of microRNAs (miRNAs) in the hematopoietic defects observed in FA patients. Initial studies showed that 3 miRNAs, hsa-miR-133a, hsa-miR-135b, and hsa-miR181c, were significantly down-regulated in lymphoblastoid cell lines and fresh peripheral blood cells from FA patients. In vitro studies with cells expressing the luciferase reporter fused to the TNF alpha 3'-untranslated region confirmed in silico predictions suggesting an interaction between hsa-miR-181c and TNF alpha mRNA. These observations were consistent with the down-regulated expression of TNF alpha mediated by hsa-miR-181c in cells from healthy donors and cells from FA patients. Because of the relevance of TNF alpha in the hematopoietic defects of FA patients, in the present study, we transfected BM cells from FA patients with hsa-miR-181c to evaluate the impact of this miRNA on their clonogenic potential. hsa-miR-181c markedly increased the number and size of the myeloid and erythroid colonies generated by BM cells from FA patients. Our results offer new clues toward understanding the biologic basis of BM failure in FA patients and open new possibilities for the treatment of the hematologic dysfunction in FA patients based on miRNA regulation. (Blood. 2012;119(13):3042-3049)
Autores: Agirre, X; Abizanda, Gloria María; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 26  Nº 7  2012  págs. 1517 - 1526
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I - II HDAC inhibitor, in acute lymphoblastic leukemia ( ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)gamma c(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)gamma c(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
Autores: Rodriguez, Paula; Román-Gómez, J.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 155  Nº 1  2011  págs. 73 - 83
The role of epigenetic mechanisms in the regulation of microRNAs (miRNAs) with a tumour-suppressor function in human neoplasms has recently been established. Several miRNAs have been found to be inappropriately regulated by DNA methylation in patients with acute lymphoblastic leukaemia (ALL). We analysed the methylation status of the three members of the MIR9 family (MIR9-1, MIR9-2 and MIR9-3) in a uniformly treated cohort of 200 newly diagnosed ALLs. MIR9 was methylated in 54% of the patients and was associated with downregulation of MIR9 (P < 0.01). Hypermethylation of MIR9 was an independent prognostic factor for disease-free survival, overall survival and event-free survival in a multivariate analysis (P < 0 01). Epigenetic downregulation of MIR9 induced upregulation of its targets, FGFR1 and CDK6, while treatment of ALL cells with FGFR1 (PD-173074) and CDK6 (PD-0332991) inhibitors induced a decrease in cell proliferation and an increase in apoptosis of ALL cells. Our results indicate that the MIR9 family is involved in the pathogenesis and clinical behaviour of ALL and provide the basis for new therapeutic strategies in the treatment of ALL, targeting the epigenetic regulation of miRNAs and/or the FGFR1 or CDK6-RB pathway directly
Autores: Agirre, X; Martín-Palanco, V.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 6  Nº 2  2011  págs. e17012
Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n¿=¿48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2'-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p¿=¿0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p¿=¿0.006) and overall survival (OS) (p¿=¿0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.
Autores: Agirre, X; Abizanda, Gloria María; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 118  Nº 21  2011  págs. 660