Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Janin M

PROVIDER: S-EPMC6851045 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Janin Maxime M Ortiz-Barahona Vanessa V de Moura Manuel Castro MC Martínez-Cardús Anna A Llinàs-Arias Pere P Soler Marta M Nachmani Daphna D Pelletier Joffrey J Schumann Ulrike U Calleja-Cervantes Maria E ME Moran Sebastian S Guil Sonia S Bueno-Costa Alberto A Piñeyro David D Perez-Salvia Montserrat M Rosselló-Tortella Margalida M Piqué Laia L Bech-Serra Joan J JJ De La Torre Carolina C Vidal August A Martínez-Iniesta María M Martín-Tejera Juan F JF Villanueva Alberto A Arias Alexandra A Cuartas Isabel I Aransay Ana M AM La Madrid Andres Morales AM Carcaboso Angel M AM Santa-Maria Vicente V Mora Jaume J Fernandez Agustin F AF Fraga Mario F MF Aldecoa Iban I Pedrosa Leire L Graus Francesc F Vidal Noemi N Martínez-Soler Fina F Tortosa Avelina A Carrato Cristina C Balañá Carme C Boudreau Matthew W MW Hergenrother Paul J PJ Kötter Peter P Entian Karl-Dieter KD Hench Jürgen J Frank Stephan S Mansouri Sheila S Zadeh Gelareh G Dans Pablo D PD Orozco Modesto M Thomas George G Blanco Sandra S Seoane Joan J Preiss Thomas T Pandolfi Pier Paolo PP Esteller Manel M

Acta neuropathologica 20190819 6

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 N ...[more]

PMID: 31428936

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Project description:There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. SGI-110 can also act as a dual inhibitor to down-regulate polycomb repressive complex 2 (PRC2) genes by demethylating their gene bodies, resulting in reactivation of PRC2 repressed genes without involvement of DNA methylation. Furthermore, it can up-regulate endogenous retroviruses to reactivate immune pathways. Finally, about 48% of frequently altered genes in primary HCC tumors can be reversed by SGI-110 treatment. CONCLUSION:Our integrative analysis has successfully linked the antitumor effects of SGI-110 to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets, and provided a rationale for combination treatments of SGI-110 with immune checkpoint therapies.

Dataset Information

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

Publications

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

Similar Datasets

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