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
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Media type:
E-Article
Title:
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
Description:
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>HOTAIR</jats:italic> as an example—that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, <jats:italic>n</jats:italic> = 67) as a model, we confirmed upregulation of <jats:italic>HOTAIR</jats:italic> in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. <jats:italic>HOTAIR</jats:italic> 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 <jats:italic>HOTAIR</jats:italic> depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer‐related <jats:italic>DPP4, RASSF1, ALDH1A3,</jats:italic> and other targets. Collectively, our data indicate that <jats:italic>HOTAIR</jats:italic> 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.</jats:p>