A protein present at high levels in more than half of all human cancers drives cell growth by blocking the expression of just a handful of genes involved in DNA packaging and cell death, according to a new study.
The researchers found that the protein, called Myc, works through a tiny regulatory molecule called a microRNA to suppress the genes’ expression. It marks the first time that a subset of Myc-controlled genes has been identified as critical players in the protein’s cancer-causing function, and suggests new therapeutic targets for Myc-dependent cancers. The study was published in Cancer Cell (2014; doi:10.1016/j.ccr.2014.06.014).
“This is a different way of thinking about the roles of microRNA and chromatin packaging in cancer,” said Dean Felsher, MD, PhD, professor of oncology and of pathology at the Stanford University School of Medicine in California. “We were very surprised to learn that the overexpression of one microRNA can mimic the cancerous effect of Myc.”
The genes identified by the researchers produce proteins that govern whether a cell self-renews by dividing, enters a resting state called senescence, or takes itself permanently out of commission through programmed cell suicide. Exquisite control of these processes is necessary to control or eliminate potentially dangerous tumor cells.
The gene encoding the Myc protein is a well-known and potent oncogene, which is a term used to describe genes that cause cancer when mutated or abnormally expressed. It regulates the expression of around 10,000 genes and microRNAs in a cell. Scientists have long known that inactivating Myc, or blocking its expression, can cause Myc-dependent cancer cells to stop growing or die, as well as cause tumor regression in mice with Myc-dependent solid cancers. This phenomenon of dependence is called oncogene addiction.
MicroRNAs are small RNA molecules (only about 22 nucleotides) that can, like Myc, regulate gene expression. Previous research had shown that Myc overexpression causes an increase in the levels of a family of microRNAs called miR-17-92.
“People have known for several years that Myc regulates the expression of microRNAs,” said Felsher. “But it wasn’t clear how this was related to Myc’s oncogenic function.”
Li found that Myc-dependent cancer cells—either grown in a laboratory dish or as a tumor in mice—in which miR-17-92 expression was locked in the ‘on’ position kept dividing even when Myc expression was blocked. This suggested that Myc works through the microRNA family to exert its cancer-causing effects.
“Myc is still a general amplifier of gene transcription and expression,” said Felsher, “but our study shows that the maintenance of the cancerous state relies on a more focused mechanism.”
“One of the biggest unanswered questions in oncology is how oncogenes cause cancer, and whether you can replace an oncogene with another gene product,” said Felsher. “These experiments begin to reveal how Myc affects the self-renewal decisions of cells. They may also help us target those aspects of Myc overexpression that contribute to the cancer phenotype.”