Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene-specific DNA methylation patterns

Bure I, Geer S, Knopf J, Roas M, Henze S, Stroebel P, Agaimy A, Wiemann S, Hoheisel JD, Hartmann A, Haller F, Moskalev E (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 57

Pages Range: 584-597

Journal Issue: 11

DOI: 10.1002/gcc.22672

Abstract

Aberrant alterations of DNA methylation are common events in oncogenesis. The origin of cancer-associated epigenetic defects is of interest for mechanistic understanding of malignant transformation and-in the long run-therapeutic modulation of DNA methylation in a locus-specific manner. Given the ability of certain long noncoding RNAs to operate as an interface between DNA and the epigenetic modification machinery which can interact with DNA methyltransferases, we hypothesized-considering HOTAIR as an example-that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, n = 67) as a model, we confirmed upregulation of HOTAIR in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. HOTAIR knockdown in GIST-T1 cells triggered transcriptional response of genes involved in the organization and disassembly of the extracellular matrix and, notably, induced global locus-specific alterations of DNA methylation patterns. Hypomethylation was induced at a total of 507 CpG sites, whereas 382 CpG dinucleotides underwent gain of methylation upon HOTAIR depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer-related DPP4, RASSF1, ALDH1A3, and other targets. Collectively, our data indicate that HOTAIR enables target specificity of DNA methylation in GIST and is capable of dual (hypo- and hypermethylation) regulation by a yet to be defined mechanism. The results further suggest the feasibility of manipulating DNA methylation in a targeted manner and are of interest in the context of epigenetic cancer therapy.

Authors with CRIS profile

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Georg-August-Universität Göttingen Germany (DE)

How to cite

APA:

Bure, I., Geer, S., Knopf, J., Roas, M., Henze, S., Stroebel, P.,... Moskalev, E. (2018). Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene-specific DNA methylation patterns. Genes Chromosomes & Cancer, 57(11), 584-597. https://doi.org/10.1002/gcc.22672

MLA:

Bure, Irina, et al. "Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene-specific DNA methylation patterns." Genes Chromosomes & Cancer 57.11 (2018): 584-597.

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