Cancer epigenetics

  • Grup Esteller Aug 2019
+34 935 572 800
Campus ICO-Germans Trias i Pujol

Josep Carreras Leukaemia Research Institute 
Can Ruti CampusCtra de Can Ruti, Camí de les Escoles s/n08916 Badalona, Barcelona
Spain

Directions

Summary

The group continues the wide-ranging work on epigenetics that Manel Esteller, the group leader, has carried out during his career until now. Current research is devoted to the establishment of the epigenome and epitranscriptome maps for normal and transformed cells, the study of the interactions between epigenetic modifications and non-coding RNAs, and the development of new epigenetic drugs for cancer therapy.

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Research

Our laboratory is one of those responsible for establishing the observation that epigenetic disruption of mRNA transcription, particularly in DNA methylation and histone modification patterns, contribute to the initiation and progression of human tumours (reviewed in Esteller, N Engl J Med 2008; Heyn and Esteller, Nat Rev Genet 2012).

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It has also been recognized that microRNAs (small non-coding RNAs that regulate gene expression by sequence-specific base pairing in mRNA targets) also play a key role in the biology of the cell, and can have an impact on the development of cancer. In this context, we characterized the first miRNA undergoing specific cancer-methylation associated silencing (Lujambio et al., Cancer Res 2007), followed by the characterization of many other miRNAs disrupted in the same manner (Lujambio et al., PNAS 2008; Davalos et al., Oncogene 2012).

We have also studied other types of ncRNA, such as subclasses of lncRNA, undergoing aberrant DNA methylation events in human cancer (Lujambio et al., Oncogene 2010; Guil et al, Nat Struc Mol Biol 2012; Liz et al., Mol Cell 2014; Diaz-Lagares et al., PNAS 2016). We have shown that sometimes these epigenetic lesions occur outside the minimal promoters and take place in enhancers (Heyn et al., Genome Biol 2016; Vidal et al, Oncogene 2017) or at cryptic internal  promoters (Vizoso et al., Nature Medicine  2015).

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Our group has also had a long-standing interest in translating the use of epigenetic knowledge gained from research into biomarkers to predict clinical outcome and to assay new drugs to reverse the distorted epigenetic landscape (Berdasco and Esteller, Nature Review Genetics 2019). For example, we have used epigenetic markers to predict response to anti-tumour therapies and following the initial observation that MGMT gene methylation predicted response to alkylating agents in glioma (Esteller et al., N Engl J Med 2000), we have found many such relationships. We have shown the relationship of methylation of MGMT with the response to alkylating agents in lymphoma (Esteller et al., J Natl Cancer Inst, 2002); of WRN with the response to irinotecan (Agrelo et al., Proc Natl Acad Sci USA, 2006); of BRCA1 with the response to PARP inhibitors (Veeck et al., J Natl Cancer Institute, 2010) and of DERL3 with the response to glycolysis inhibitors (Lopez-Serra et al., Nature Communications, 2014). Methylation of SRBC (Moutinho et al. J Natl Cancer Institute, 2014) and SLFN11 (Nogales et al., Oncotarget 2015) have also been identified as resistance markers for platinum derivatives in human tumours and the regulator of EGFR TBC1D16 has been identified as a sensitizer for therapies with BRAF and MEK inhibitors (Vizoso et al., Nature Medicine 2015). Recent discoveries indicate that SVIP is related to the response to GLUT1 inhibitors (Llinas-Arias et al. JCI Insight 2019).

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Continuing with this translational side of our work, we are also interested in the development and study of new epigenetic drugs that target DNA methylation and histone modification writers, readers and erasers and could have an anti-cancer effect (Lara et al Oncogene 2008; Zubia et al Oncogene 2009; Huertas et al., Oncogene 2012; Perez-Salvia et al., Oncotarget 2017; Perez-Salvia et al., Haematologica 2018).

Interestingly, the “repertoire” of epigenetic modifications of DNA is fairly limited, as we recently reviewed (Heyn and Esteller, Cell 2015). In sharp contrast, more than one hundred post-transcriptional modifications occur in RNA (Esteller and Pandolfi, Cancer Discovery 2017; Davalos et al., Cell 2018). Until very recently it was almost impossible to make a good map of the epigenetic modifications of the RNA molecule, which hampered many studies in this area and prevented advances in the study of the significance of each RNA modification. However, recent methodologies now allow the study of the so-called epitranscriptome. In this field, we have shown aberrant RNA editing mediated by ADAR1 amplification (Anadon et al., Oncogene 2016) and altered RNA decapping mediated by NUDT16 epigenetic silencing (Anadon et al., Leukemia 2017). Knowledge in this area is limited and its study is the focus of intense research in the lab.

We have also a long-standing vocation for research in monogenic disorders affecting epigenetic genes (Urdinguio et al., Lancet Neurol. 2009), particularly in Rett syndrome. The disease is associated with a germline mutation in MECP2, a protein that it is attracted to methylated DNA.  Over the years, we have identified the gene targets for MECP2 (Ballestar et al., EMBO J 2013; Petazzi et al. RNA Biol. 2013, Neurobiol Dis. 2014), studied the genomics of Rett syndrome in detail (Saez et al., Genet Med 2016; Lucariello et al., Hum Genet 2016) and developed pre-clinical drug studies (Szczesna et al., Neuropsychopharmacology et al., 2014; Jorge-Torres et al., Cell Reports 2018). In a similar context, we are also curious about the epigenomic profiles of common diseases such as cardiovascular alterations (Zaina et al., Circ Cardiovasc Genet. 2014; Valencia-Morales et al., BMC Med Genomics 2015) and Alzheimer and other neurodegenerative diseases (Sanchez-Mut et al., Brain et al., 2013; Hipoccampus 2014; Transl Psychiatry. 2016; Nature Medicine, 2018).

Finally, we have a strong interest in the establishment of new epigenomic platforms to elaborate comprehensive DNA methylome maps, our lab is the pioneer in the validation of the commonly used DNA methylation microarrays such as the 450K (Sandoval et al., Epigenetics 2011) and the EPIC/850K (Moran et al. Epigenomics 2016). The use of these approaches has made several breakthroughs possible, such as:  the establishment of DNA methylation signatures that are predictive of early dissemination in lung cancer (Sandoval et al., JCO 2010); the diagnosis of the tumor type in Cancer of Unknown Primary (CUP) (Moran et al., Lancet Oncology 2016); or better understanding of the response to anti-PD1 immunotherapy (Duruisseaux et al., The Lancet Respiratory Medicine 2018).

Awards

2019       Lansdowne Lecture Award, University of Victoria, British Columbia, Canada

2018       Scientific Achievements Prize, Foundation for the Excellence in Oncology (ECO)

2018       Scientific Innovation Award Team in Clinical Research, Pfizer Foundation

2018       Award for the Best Science and Humanities Dissemination Activities by the Board of Trustees and the Doctors' Senate of the University of Barcelona (UB)

2018       Innovation Health Award in Oncology by Celgene Endowment

2017       “Carlemagne Falcon” Award, Girona, Catalonia

2017       Best Ideas in Health, Epitranscriptome, Diario Medico

2016       Honour Gold Medal, Government of Catalonia (Generalitat de Catalunya)

2016       Premi Internacional de Catalunya, Generalitat de Catalunya

2016       Best Ideas in Health, EPICUP, Diario Medico

2016       European Research Council Proof of Concept Grant

People

Selected publications

Janin M, Ortiz-Barahona V, de Moura MC, Martínez-Cardús A, Llinàs-Arias P, Soler M, Nachmani D, Pelletier J, Schumann U, Calleja-Cervantes ME, Moran S, Guil S, Bueno-Costa A, Piñeyro D, Perez-Salvia M, Rosselló-Tortella M, Piqué L, Bech-Serra JJ, De La Torre C, Vidal A, Martínez-Iniesta M, Martín-Tejera JF, Villanueva A, Arias A, Cuartas I, Aransay AM, La Madrid AM, Carcaboso AM, Santa-Maria V, Mora J, Fernandez AF, Fraga MF, Aldecoa I, Pedrosa L, Graus F, Vidal N, Martínez-Soler F, Tortosa A, Carrato C, Balañá C, Boudreau MW, Hergenrother PJ, Kötter P, Entian KD, Hench J, Frank S, Mansouri S, Zadeh G, Dans PD, Orozco M, Thomas G, Blanco S, Seoane J, Preiss T, Pandolfi PP, Esteller M

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program.

Acta Neuropathol. 19 Aug 2019, . Epub 19 Aug 2019
Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.
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Bueno-Costa A, Piñeyro D, Soler M, Javierre BM, Raurell-Vila H, Subirana-Granés M, Pasquali L, Martinez-Climent JA, Esteller M

B-cell leukemia transdifferentiation to macrophage involves reconfiguration of DNA methylation for long-range regulation.

Leukemia 12 Nov 2019, . Epub 12 Nov 2019More information
Rosselló-Tortella M, Llinàs-Arias P, Sakaguchi Y, Miyauchi K, Davalos V, Setien F, Calleja-Cervantes ME, Piñeyro D, Martínez-Gómez J, Guil S, Joshi R, Villanueva A, Suzuki T, Esteller M

Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Proc Natl Acad Sci U S A. 2020 Aug 25 1 Aug 2020, 117(34):20785-20793 .
Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNAs (mRNAs). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in -1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology
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Current projects

ACRCelerate: Colorectal Cancer Stratified Medicine Network

Project leader:Manel Esteller
Code:A26825
Funding:
Start date:01/11/2018
End date:31/10/2023

EPINMUNE: Identification of epigenetic biomarkers for prediction of response to immunotherapy

Project leader:Verónica Davalos Vega
Code:INVES208DAVA
Funding:
Start date:01/06/2019
End date:30/11/2021