Target found for gastric cancer associated with EBV

Tuesday, 19 September, 2023

Target found for gastric cancer associated with EBV

Scientists at The Wistar Institute and their collaborators have discovered a potential target for gastric cancer associated with Epstein–Barr virus (EBV), with their study results published in the journal mBio.

Associate Professor Italo Tempera and his colleagues set out to investigate the epigenetic characteristics of EBV-associated gastric cancer, or EBVaGC. In evaluating EBVaGC’s epigenetics — the series of biological signals associated with the genome that determines whether a given gene is expressed — the Tempera lab highlighted a target that could serve as a future treatment for this type of cancer.

“What we have identified is essentially a self-destruct button within this kind of cancer, and our paper shows that we figured out how to press that self-destruct button,” Tempera said. “Normally, a latent virus that reactivates and starts to kill cells is a bad thing. But by switching that viral lytic process back on in these cancer cells by using epigenetic signalling, we’re effectively getting the virus to kill the cancer cells that it’s responsible for in the first place.”

In EBVaGC, the cancer cells’ DNA is hypermethylated: the DNA contains a high percentage of cytosine with a 5-methyl group attached to it (relative to normal, unmethylated cytosine). As a silencer of gene expression, DNA methylation allows EBV to remain latent. This methylation pattern plays a significant role in regulating the EBV latency-lysis cycle within the cancer cells. DNA methylation, as an epigenetic factor, usually functions as a gene-silencing mechanism, particularly in certain regions of the genome; a methylated gene still exists within the genome, but methylation can prevent the protein the gene encodes from being transcribed.

To disrupt this epigenetic profile, the researchers turned to decitabine, a compound known for its ability to reduce DNA methylation levels (ie, to hypomethylate the DNA). Tempera and his co-authors treated two cell lines that were derived from EBVaGC tumours with decitabine. The cell lines that received the treatment demonstrated massive reductions in DNA methylation across the genome relative to the control as assessed by a variety of epigenetic assay techniques.

In observing the effects of decitabine treatment on EBVaGC, Tempera’s team found a significant disruption of the cancer’s epigenetic profile. The EBV genome within EBVaGC treated with decitabine resulted in widespread, mostly uniform hypomethylation of the EBVaGC epigenome (with a few regional exceptions).

The researchers also discovered that the hypomethylating effect of decitabine treatment reactivated the lytic cycle of the latent EBV in the cancer cells. Because lysis is lethal to cells, the epigenetic reactivation of lysis within gastric cancer associated with EBV offers a promising potential treatment for the specific subset of EBVaGC.

“Now we know that we can use the epigenome of Epstein–Barr virus against the gastric cancer that it affects,” Tempera said. “That’s an exciting potential cancer therapy we have as a result of investigating the interplay between epigenetic patterns and disease life cycle.”

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