Computer simulations revealthe structure and dynamics of chemical signal that triggers metastatic cancer

In cancer and other pathological diseases, researchers are discovering that packaging is important: specifically, how DNA – about two meters long when unwound and stretched – coils up and compacts neatly inside the nucleus of a cell.

What they've learned is that molecular signals that control the packaging of DNA are critical to the activation and silencing of genes in the human body – a process generally described as epigenetics.

Molecular Dynamics simulation shows that oxygen molecules reach the active site of Lysine Specific Demethylase 1 although substrate peptides (black, H3 histone tail & orange, SNAIL1 protein) are bound (Riccardo Baron et al., UC San Diego)

Now, a team of researchers from UC San Diego and the University of Pavia in Italy, with the help of high-performance computers housed at the San Diego Supercomputer Center (SDSC), have captured the chemical structure of one such signal – in static crystal form and in motion – which is at the heart of a variety of morphological events including the rapid movement of cells during embryonic development, wound healing, and cancer.

The results offer a potentially new path to combat metastatic cancer by blocking the activity of this epigenetic signal, which, among other things, has been shown to silence a gene responsible for cell-to-cell adhesion, a ''molecular glue,'' thus allowing cancer cells to spread.

''Our study opens the understanding of the molecular interaction and dynamics to be targeted to develop epigenetic drugs which hopefully will lead in the future to potent drugs against cancer,'' said J. Andrew McCammon, Joseph Mayer Chair of Theoretical Chemistry and Professor of Pharmacology at UC San Diego and a Howard Hughes Medical Institute Investigator.

Historically, cancer researchers have generally focused on genetic mutations, specific changes in DNA which alter the function of the proteins they encode; studies ultimately have yielded several targeted drugs based on this approach. But treatments for many forms of cancer remain limited, prompting the search for other novel approaches. In particular, some have turned to epigenetics and processes that activate or silence genes by altering the physical structure of DNA -- how it's packaged -- leaving its message or sequence intact.