Cancer cells that resist chemotherapy and become “persisters” remain a daunting clinical challenge. They appear to attain and retain their staying power largely through nongenetic mechanisms, which remain poorly defined. To understand these mechanisms better, scientists at the Curie Institute in Paris have studied cancer cells that occur in triple-negative breast cancer types associated with the highest risk of recurrence. Specifically, the scientists monitored epigenomes, transcriptomes, and lineages with single-cell resolution.

This work enabled the scientists to demonstrate that the repressive histone mark H3K27me3 (trimethylation of histone H3 at lysine 27) regulates cell fate at the onset of chemotherapy. Essentially, the scientist showed that epigenetic landscapes play a crucial role in shaping the potential of cancer cells to respond to initial therapy.

Detailed results appeared in Nature Genetics, in an article titled, “H3K27me3 conditions chemotolerance in triple-negative breast cancer.”

“We report that a persister expression program is primed with both H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation,” the article’s authors wrote. “We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy.”

The scientists, who were led by Leïla Perié, PhD, and Céline Vallot, PhD, used the word “lock” advisedly. They found that in the absence of treatment, epigenomic marks “lock” genes, preventing them from being expressed. However, in some cells, after treatment commences, the lock “jumps,” and the cells become insensitive to treatment. If the lock can be prevented from jumping, all cancer cells remain sensitive to treatment.

In their article, the scientists presented evidence for this phenomenon. “Preventing H3K27me3 demethylation [during chemotherapy],” they reported, “inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo.”

This finding could inform the development of epigenetic drugs (epi-drugs). In animal models, epi-drugs have been shown to inhibit the removal of epigenetic marks. The epi-drugs that have shown promise in animal models still need to be adapted for human use.

Epigenetic marks are chemical modifications of the DNA or associated proteins that determine the expression of the genes and thus a cell’s identity. This information, which is central from the development of the embryo onwards, leads to changes in how our genes are expressed without affecting their sequence. By modifying its epigenome, the cell can adapt quickly to its environment.

The epigenome’s involvement in resistance to cancer treatment has been clearly demonstrated by the scientists involved in the current study. They are now actively seeking how to apply their epigenomic findings to the development of new epi-drugs. If future clinical trials are convincing, scientists imagine that these epi-drugs could be used in conjunction with chemotherapies to prolong their effectiveness in patients.

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