Chromatin-regulating enzyme found as a major driver of common lung cancer

An enzyme that regulates chromatin has been shown by in-depth interdisciplinary studies as a major driver of a common type of lung cancer. Drugs that target the enzyme may improve treatment and survival rates for this particular cancer.

“Squamous cell carcinoma represents nearly a third of all lung cancers in humans,” said Lukasz Jaremko, a KAUST structural biologist, who led the research with colleagues at Stanford University and the University of Texas MD Anderson Cancer Center, US “Our co-structure and dynamics studies, including enzymatic activity studies, genetic analyzes, and mouse model and human cell results, all identify the enzyme histone-lysine N-methyltransferase (NSD3) as a major driver of cancer, “he says.

As part of the studies, a Ph.D. Student Vladlena Kharchenko, a member of the Jaremko Laboratory, used a nuclear reconstruction spectroscope to perform an experimental assessment of the structure and dynamics of both normal NSD3 and the hyperactive mutant involved in driving cell carcinoma squamous cells.

The mutation did not appear to affect the static structure of the enzyme. However, using the nuclear Overhauser effect, we were able to show that hyperactive mutations induced movement changes in part of the NSD3 enzyme, allowing two methyl molecules to attach to the histone tail in chromatin. This ultimately deregulates cancer-promoting genes in some lung cancers. “

Lukasz Jaremko, KAUST Structural Biologist

Scientists have long noticed that many genes within a specific area on chromosome 8 are involved in cancer formation. One gene in particular, FGFR1, has received much attention as a potential driver of lung cancer. But clinical trials inhibiting the protein encoded by this gene have been disappointing.

“Our studies explain the molecular underpinnings of NSD3’s enzymatic hyperactivity, a macsere danse, and vaguely prove that NSD3, not the previously suspected FGFR1, is the main driver for squamous cell carcinoma of the lung , “said Jaremko.

The collaborative studies also found that NSD3 was susceptible to a type of anticancer drug called bromodomine inhibitors. But there is still a need for guards that specifically target NSD3, making it an explicit target for drug screening campaigns.

The team wants to improve the molecular understanding of the function of NSD3 in chromatin and cells. “Our study shows that the molecular dynamics features of cancer study are complex and interesting,” says Kharchenko. “It also shows that there is more to be understood about the role of NSD3 at the atomic level before we can make a robust treatment. develop specific NSD3. “