Found 7 publicacions matching the indicated search criteria.
Guil S, Esteller M
PRC2 Loss and DNMT Inhibition Boost Viral Mimicry in Cancer.
Cancer Discov2 Sep 2022, 12(9)2020-2022.
In this issue of Cancer Discovery, Patel and colleagues explore the synergistic lethality of PRC2 inactivation and DNMT inhibition in malignant peripheral nerve sheath tumor cells. Reactivation of retrotransposons under this dual control suggests that the viral mimicry response contributes to enhanced cytotoxicity with potential clinical implications. See related article by Patel et al., p. 2120 (5).
The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer.
Seminars in Cancer Biology25 May 2022, . Epub 25 May 2022
RNA binding proteins that act at the post-transcriptional level display a richness of mechanisms to modulate the transcriptional output and respond to changing cellular conditions. The family of IGF2BP proteins recognize mRNAs modified by methylation and lengthen their lifecycle in the context of stable ribonucleoprotein particles to promote cancer progression. They are emerging as key 'reader' proteins in the epitranscriptomic field, driving the fate of bound substrates under physiological and disease conditions. Recent developments in the field include the recognition that noncoding substrates play crucial roles in mediating the pro-growth features of IGF2BP family, not only as regulated targets, but also as modulators of IGF2BP function themselves. In this review, we summarize the regulatory roles of IGF2BP proteins and link their molecular role as m
Siqueira E, Obiols-Guardia A, Jorge-Torres OC, Oliveira-Mateos C, Soler M, Ramesh-Kumar D, Setién F, van Rossum D, Pascual-Alonso A, Xiol C, Ivan C, Shimizu M, Armstrong J, Calin GA, Pasterkamp RJ, Esteller M, Guil S
Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome.
Mol Ther Nucleic Acids8 Mar 2022, 27621-644. Epub 22 Dec 2021
Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in affected individuals and in vitro human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value.
Soler M, Davalos V, Sánchez-Castillo A, Mora-Martinez C, Setién F, Siqueira E, Castro de Moura M, Esteller M, Guil S
The transcribed ultraconserved region uc.160+ enhances processing and A-to-I editing of the miR-376 cluster: hypermethylation improves glioma prognosis.
Mol Oncol19 Oct 2021, . Epub 19 Oct 2021
Transcribed ultraconserved regions (T-UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T-UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T-UCR in gliomas and mechanistically define a novel RNA-RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR-376 cluster. This includes the positive regulation of primary microRNA (pri-miRNA) cleavage and an enhanced A-to-I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR-376-regulated genes, including the transcriptional coregulators RING1 and YY1-binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower-grade gliomas, highlighting the importance of T-UCRs in cancer pathophysiology.
Trends Mol MedApr 2020, 26(4)352-354. Epub 18 Feb 2020
In a recent iScience paper by Fan et al., the long noncoding (lnc)RNA CISAL is shown to form a DNA-RNA triplex and to directly regulate BRCA1 transcription, thereby increasing cisplatin sensitivity and serving as a treatment efficacy biomarker. This opens promising avenues of research from both mechanistic and translational perspectives.
Oliveira-Mateos C, Sánchez-Castillo A, Soler M, Obiols-Guardia A, Piñeyro D, Boque-Sastre R, Calleja-Cervantes ME, Castro de Moura M, Martínez-Cardús A, Rubio T, Pelletier J, Martínez-Iniesta M, Herrero-Martín D, Tirado OM, Gentilella A, Villanueva A, Esteller M, Farré L, Guil S
The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition.
Nat Commun4 Sep 2019, 10(1)3979. Epub 4 Sep 2019
One largely unknown question in cell biology is the discrimination between inconsequential and functional transcriptional events with relevant regulatory functions. Here, we find that the oncofetal HMGA2 gene is aberrantly reexpressed in many tumor types together with its antisense transcribed pseudogene RPSAP52. RPSAP52 is abundantly present in the cytoplasm, where it interacts with the RNA binding protein IGF2BP2/IMP2, facilitating its binding to mRNA targets, promoting their translation by mediating their recruitment on polysomes and enhancing proliferative and self-renewal pathways. Notably, downregulation of RPSAP52 impairs the balance between the oncogene LIN28B and the tumor suppressor let-7 family of miRNAs, inhibits cellular proliferation and migration in vitro and slows down tumor growth in vivo. In addition, high levels of RPSAP52 in patient samples associate with a worse prognosis in sarcomas. Overall, we reveal the roles of a transcribed pseudogene that may display properties of an oncofetal master regulator in human cancers.
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.