Squamous cell lung cancer driven by DNA methylation

Lung squamous cell cancer (LUSC) accounts for nearly one-third of lung cancer cases. The amplification of the genomic region 8p11-12 has been linked with the disease, but so far researchers haven’t been able to pin down the culprit gene in that region. The FGFR1 gene seemed a likely candidate, but clinical trials targeting it have proven unsuccessful.

Now, a team of researchers from King Abdullah University of Science and Technology, Stanford University, and the University of Texas have shown that mutation of another gene located in 8p11-12 causes LUSC. NSD3 codes for a methyltransferase, an enzyme responsible for attaching a molecule known as methyl to DNA-scaffolding proteins called histones. Unlike FGFR1, NSD3 is expressed more strongly when 8p11-12 is amplified in LUSC, making it a likely candidate.

The researchers first showed that depleting NSD3 in LUSC cell cultures inhibited tumour growth. Likewise, knocking down NSD3 expression in an engineered mouse model of LUSC reduced tumour growth and cell proliferation, while knocking down FGFR1 did not.

“Until now, NSD3 was considered a rather boring and uninteresting methyltransferase compared to related genes,” says KAUST’s Łukasz Jaremko, one of the study’s lead authors. However, the team clearly showed that NSD3-mediated methylation is linked with LUSC.

They identified a mutation in NSD3 that made it more effective at methylation. Mouse model of LUSC with the more active version of NSD3 had accelerated tumour growth, more cell proliferation, and less cell death, leading to a 30% reduction in their lifespan. “The activity of NSD3 in dimethylation is the main driving force of generating LUSC cells and transforming healthy ones into cancer cells,” says Jaremko. These findings link NSD3-mediated methylation with LUSC, and show that it affects the clinical outcome of the disease.

Finally, the researchers screened a library of 285 cancer drugs to see if any were more effective against cells with increased NSD3 expression. A group of drugs known as bromodomain inhibitors had a stronger effect on cells with increased NSD3, suggesting that these may be an effective therapy for LUSC cases with NSD3 malfunction. “One cannot expect that this therapy is going to be fully effective, as it relies on a complex interaction network of the NSD3 protein,” says Jaremko. “Nevertheless, this is a hint.”

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