Scientific research at the Stowers Institute for Medical Research reveals a potential link between cellular metabolism and gene expression. As per the researchers, this link offers potentially far-reaching implications for cancer risk prediction and treatment.
The key protein complex studied by the scientists is called Serine-responsive SAM-containing Metabolic Enzyme complex (SESAME). Although it is found in yeast, scientists believe a human analog exists. SAM stands for S-adenosylmethionine. It is a compound crucial to histone methylation. The study was published in the journal Molecular Cell.
The basic purpose of the study was to understand more about the pyruvate kinase PKM2. Note that it plays very important roles in tumorigenesis. The researchers used a yeast model because the complexity of mammalian systems makes it difficult to get a clear clue.
The scientists were able to find that the PKM2 homolog in yeast, Pyk1, forms a novel complex with other metabolic enzymes. The research team called this complex SESAME.
Cancer cells are different from normal cells. They depend on elevated aerobic glycolysis for rapid and continuous growth. Pyruvate kinase M2 (PKM2) is one of the key enzymes for glycolysis. PKM2 catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. The former is a high-energy phosphate-containing compound and the latter is the final product of glycolysis.
In addition, PKM2 also provides a great deal of energy in the process. It has an alternative splice variant called PKM1. When swapped in, PKM1 can reverse the aerobic glycolysis and alleviate the rate of tumorigenesis. With this information, you must not be surprised to know that PKM2 has become an attractive target for anticancer therapies. However, PKM2 not only regulates glycolysis but also phosphorylates histone H3 threonine 11 (H3T11). It is a protein that mutates chromosomes and affects gene regulation.
What is the connection between the two?
This might indicate a link between cellular metabolism and gene regulation and, if so, what is the connection? The answer involves the following three,
- A glycolysis-generated amino acid called serine
- A yeast homolog of PKM2 called Pyk1
Previous research studies reveal that serine metabolic enzymes are important in the survival and proliferation of cancer cell. However, the underlying mechanism is unknown. These studies also suggest the role of serine in activating PKM2 and, consequently, converting PEP to pyruvate during glycolysis.
The study presents SESAME as the first example of a protein complex, directly regulating cellular metabolism and chromatin modification by utilizing its own enzyme subunits. Researchers have found that SESAME links the ability to sense serine to the regulation of genetic material or chromosomes. Therefore, it suggests a potential target for detecting and treating cancers.
Although the study utilized yeast models for experimentation, the team believes that the same relationship holds true for humans. This is because most components of SESAME are conserved from yeast to mammals. Furthermore, researchers think that PKM2 could also form a complex like SESAME, and may shed light on why cancer cells require PKM2 and serine metabolism. Note that glycolysis and the pathway of glucose-derived serine metabolism are already in use as human cancer therapy targets.
SESAME enzymes could provide new targets for cancer therapy by promoting the PKM2 feedback loop. The researchers are looking forward to identifying human SESAME. In this way, they can provide evidences using human cells as well.