An epigenetic blueprint reveals how aggressive MYC amplification fuels cancer

Researchers at Fox Chase Cancer Center's Cancer Epigenetics Institute discovered the epigenetic mechanisms controlling MYC gene amplification, a common feature in aggressive tumors. MYC, a protein linked to 70% of human malignancies, has been deemed "undruggable" due to its lack of a binding pocket for traditional therapies. Instead of targeting the protein, the researchers focused on the gene's structural assembly line, manipulating the chromatin environment.

Two proteins, KDM4C and SETD2, regulate the amplification process by managing DNA stability and accessibility. When SETD2 is lost, KDM4C improperly interacts with the MYC gene, causing its overexpression. The study found that KDM4C recruits the cell's DNA-copying machinery, leading to repeated copying of the MYC gene. This process can produce extra MYC gene copies and extrachromosomal DNA, contributing to tumor development.

The research also revealed that when cells lose their ability to undergo programmed cell death, abnormal MYC amplifications can continue to grow. This discovery suggests that MYC amplification is an actively regulated process rather than a random event, opening new avenues for therapeutic interventions targeting this epigenetic mechanism.