Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center led an international team that discovered that cancer stem cell properties are determined by epigenetic changes.
The study, which was carried out on human tumor samples and mouse models, is published in the Proceedings of the National Academy of Sciences. The team reports that Lysine-Specific Demethylase 1 (LSD1) turns off genes required to maintain cancer stem cell properties in glioblastoma, a highly aggressive form of brain cancer. This epigenetic activity helps explain how glioblastoma can resist treatment. In addition, drugs that modify LSD1 levels could provide a new approach to treating glioblastoma, according to the researchers.
The investigators first noticed that genetically identical glioblastoma cells isolated from patients differed in their tumorigenicity when transplanted to mouse models. This observation suggested that epigenetics, rather than specific DNA sequences, determines tumorigenicity in glioblastoma cancer stem cells.
“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Clark Chen, M.D., Ph.D., associate professor of neurosurgery and vice-chair of research and academic development at UC San Diego School of Medicine.
Probing further, Dr. Chen's team discovered that the epigenetic factor determining whether or not glioblastoma cells can proliferate indefinitely as cancer stem cells is their relative abundance of LSD1, which removes methyl groups from DNA, turning off a number of genes required for maintaining cancer stem cell properties, including MYC, SOX2, OLIG2, and POU3F2.
“This plasticity represents a mechanism by which glioblastoma develops resistance to therapy,” noted Dr. Chen. “For instance, glioblastomas can escape the killing effects of a drug targeting MYC by simply shutting it off epigenetically and turning it on after the drug is no longer present. Ultimately, strategies addressing this dynamic interplay will be needed for effective glioblastoma therapy.”
Dr. Chen and one of the study's first authors, Jie Li, Ph.D., note that the epigenetic changes driving glioblastoma are similar to those that take place during normal human development.
“Though most cells in our bodies contain identical DNA sequences, epigenetic changes help make a liver cell different from a brain cell,” said Dr. Li, an assistant project scientist in Chen's lab. “Our results indicate that the same programming processes determine whether a cancer cell can grow indefinitely or not.”