Histone Mutation Sufficient to Trigger Cancer Development

A missense mutation in a histone protein has been shown to be able to prompt the development of cancer cells without any change to the DNA of the cells that are involved.

Histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and playing a role in gene regulation. This enables the compaction necessary to fit the large genomes of eukaryotes inside cell nuclei: the compacted molecule is 40,000 times shorter than an unpacked molecule.

Missense mutations (that change one amino acid for another) in the histone H3 can produce a so-called oncohistone and are found in a number of pediatric cancers. For example, the lysine-36–to-methionine (K36M) mutation is seen in almost all chondroblastomas, benign tumors that arise in cartilage typically during adolescence.

Investigators at the Rockefeller University (New York, NY, USA) inserted the H3 histone mutation into mouse mesenchymal progenitor cells (MPCs), which generate cartilage, bone, and fat and then injected the mutant cells into living mice. The animals developed the tumors rich in MPCs, known as an undifferentiated sarcoma.

The investigators reported in the May 13, 2016, issue of the journal Science that K36M mutation impaired the differentiation of mesenchymal progenitor cells and generated undifferentiated sarcoma in vivo. K36M mutant nucleosomes inhibited the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibited H3K36 methylation, was sufficient to phenocopy the H3K36M mutation.

The mutation inhibited enzymes that normally tag the histone with methyl groups, allowing genes to be expressed normally. In response to this lack of modification, another part of the histone becomes over-modified (tagged with too many methyl groups). "This leads to an overall resetting of the landscape of chromatin, the complex of DNA and its associated factors, including histones," said senior author Dr. Peter Lewis, now assistant professor of biomolecular chemistry at the University of Wisconsin (Madison, USA). "This resetting is what locks the cell into its proliferative state."

"Once researchers understand more about these pathways," said Dr. Lewis, "they can consider ways of blocking them with drugs, particularly in tumors such as MPC-rich sarcomas--which, unlike chondroblastoma, can be deadly. In fact, drugs that block the pathways may already exist and may even be in use for other types of cancers."

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