International Business Department           Liu Bojia           September 20, 2023

  Pancreatic cancer is one of the most aggressive and deadly types of tumors, with a 5-year survival rate of only about 11%. Pancreatic cancer is also known as the "king of cancers" because of its high mortality rate. According to a Cancer Research study of U.S. cancer patients, pancreatic cancer has become the second leading cause of cancer-related deaths in the U.S., with more than 90 percent of pancreatic cancer cases being pancreatic ductal adenocarcinoma (PDAC).

  But why is pancreatic cancer more dangerous than other tumor types? A comprehensive analysis of studies from Johns Hopkins University had found that more than 200 proteins have a two-fold elevated expression in pancreatic cancer cells compared to normal pancreatic cells, many of which show elevated phosphorylation.

  Trying to boost protein levels isn't something that pancreatic cancer just turns up, though; it needs to regulate the protein expression system by controlling additional mechanisms. In a new study in Nature Communications, scientists have found that pancreatic cancer cells use molecular regulatory mechanisms called enhancers very cleverly to get more of the proteins they need.

  An enhancer is a piece of non-coding sequence on DNA that, although it doesn't produce proteins on its own, as the name suggests, acts to enhance the expression levels of other coding genes. When a regulatory element binds to an enhancer, the enhancer's switch is flipped, which then activates specific gene expression.

  Among the enhancers, those that are most active are often called "super-enhancers," which can activate the expression of multiple genes at the same time with high intensity and change the state of the cell in a short period of time, a change that is critical for cell growth and proliferation. Cancer cells, which are particularly fond of uncontrolled proliferation, value this characteristic of super enhancers and use them repeatedly. According to existing data, super enhancers have become one of the key factors driving tumorigenesis.

  And the new study re-analyzed 16 different human pancreatic cancer cell lines, and as a result, a rise in the activity of numerous super-enhancers was clearly observed, among which a super-enhancer related to the HNRNPF gene attracted the authors' attention, and compared with normal pancreatic ductal cells, the expression of HNRNPF was up-regulated in both early- and late-stage PDAC cells, and with the degree of tumor progression, the HNRNPF is progressively expressed at higher and higher levels.

  And behind this change in expression, the super-enhancer signaling becomes stronger in parallel. If the super-enhancers in pancreatic cancer cells are disrupted, it can directly cause an 80% decrease in HNRNPF transcript levels and a 35% decrease in protein levels. As a result, the proliferation of cancer cells is significantly slowed down, and disrupting just a single super-enhancer associated with HNRNPF is enough to reduce tumor growth by more than 80%. The researchers confirmed that disrupting super-enhancers can have a similar effect as directly inhibiting HNRNPF.

  Downstream of HNRNPF, two other genes that can promote tumor growth are affected, creating a large network of super-enhancer effects. The researchers point out that the ultimate controller of this network is the familiar classic oncogene Myc, and although it is more difficult for drugs to work against Myc, it could be simpler to stop tumors from developing if they could start with the super-enhancers.