More than 80 years ago, German physiologist and physician Otto Warburg hypothesized that cancer cells consume and use nutrients to drive their growth differently than their normal counterparts, a process called the Warburg effect. This work, for which he was awarded the Nobel Prize in 1931, laid the foundation for the field of cancer metabolism. Today, the metabolic rewiring of tumor cells is being carefully dissected so that new therapies aimed at exploiting or disrupting cancer metabolism can be developed and translated into clinical practice.
In response to starvation or caloric restriction, animals – including humans – undergo a series of changes to their metabolism. Among the cascade of events that occur, it is known that major changes in gene expression – that is, the conversion of DNA code into functional proteins – are critical for carrying out the ensuing metabolic changes. Until recently, the molecular signals that link metabolism, in either normal or cancer cells, to gene expression have been virtually unknown.
A pioneering study led by Yingming Zhao, PhD, professor of the Ben May Department for Cancer Research, published in latest issue of Molecular Cell has provided some important clues to how metabolism controls gene expression.
Key to their discovery was identification of a new type of post-translational modification on histone proteins called lysine b -hydroxybutyrylation (abbreviated Kbhb). Post-translational modifications are chemical marks added onto proteins and are known to have profound effects on protein function. Histone proteins comprise the spools around which DNA strands are wound and compacted in cell nuclei. Collectively these DNA and protein complexes are referred to as chromatin. In general, histone marks alter chromatin structure and accessibility of DNA to factors that turn gene expression on or off. Marks on DNA and histones, collectively referred to as “epigenetic” modifications, modulate gene expression without changing the actual genetic (DNA) sequence.
In this case, the epigenetic mark Zhao identified tags lysine amino acids specifically on histone proteins. How precisely is the Kbhb mark related to metabolism? Zhao and colleagues demonstrated that Kbhb is derived from the metabolite b-hydroxybutyrate, a type of ketone body. Ketone bodies, like b-hydroxybutyrate, are known to be major source of energy after starvation. Kbhb marks were dramatically increased in tissues and cell models subjected to fasting or nutrient deprivation, consistent with the high levels of b-hydroxybutyrate. Beyond serving as an energy source, b-hydroxybutyrate is elevated in untreated diabetes and has been linked previously to some aspects of cancer cell behavior.
The discovery of Kbhb opens up previously unimagined avenues for research on the role of b-hydroxybutyrate in disease. Ketone bodies, including b-hydroxybutyrate, are thought to be key mediators of a diverse set of biological effects caused by ketogenic diets. In fact, ketogenic diets are being tested in patients with brain cancer, and there are many ongoing clinical trials assessing ketogenic diets as potential therapeutic approaches for a variety of malignancies, cardiovascular disease and neurological disease.
The team also observed that Kbhb marks were induced at specific genomic regions in response to starvation, specifically regions that encode enzymes and proteins important in metabolic pathways. Altogether, they identified 44 histone Kbhb sites from mouse and human cells. One of these sites, a specific Kbhb mark on histone H3 lysine 9 (H3K9bhb), distinguished a unique set of regulated genes from genes marked by other well-characterized histone epigenetic modifications (e.g., H3K9ac and H3K4me3). With broad implications across the epigenetics field, these results suggests that Kbhb marks may have very unique functions in chromatin remodeling and controlling gene expression that distinguish them from other types of epigenetic marks.
Taken together, this research supports the concept that the newly identified Kbhb modification serves as a way for cells to adapt to changes in energy sources by rewiring epigenetic programs and fine-tuning gene expression.
According to Zhao, “Histone modification plays a critical role in gene expression and to understand this we need to have a whole description of histone marks.”
Creating this complete picture may be what we need to fully capitalize on Warburg’s seminal discoveries about cancer metabolism. By identifying one way that normal and tumor cells transmit information about their energy source into changes in gene expression – and resulting biochemical and physiological changes – scientists are one step closer to developing therapeutic interventions. And since drugs that target other epigenetic modifications are being used or tested currently for a wide range of cancer types, there is optimism that Kbhb marks can be added to the list in the future.
In the same issue of Molecular Cell, Zhao and his colleagues published two additional studies characterizing histone post-translational modifications. In the first, the team showed that a dynamic combination of acetylation and butyrylation marks on histone H4 dictates chromatin remodeling and gene expression during sperm development. In the second report, the researchers identified a protein (AF9 YEATS domain) responsible for recognizing a certain histone modification called crotonylation. These mechanistic insights further set the stage for understanding the functional significance of these modifications in normal cells and how they might be disrupted in disease.