Deciphering connections between cancer metabolism, the epigenome and cellular stress
In a cross-departmental collaboration with the Institute for Diabetes and Cancer (IDC) and the Institute of Virology (Viro), researchers from the Schneider lab (Institute of Functional Epigenetics, IFE) have discovered a novel axis connecting metabolism and transcriptional regulation.
Cancer cells possess the remarkable ability to convert glucose into lactate more efficiently than healthy cells, which helps them grow rapidly. Pyruvate kinase (PK) is a critical enzyme involved in glucose metabolism and thus a promising therapeutic target.
Embarking on a quest, researchers from the Schneider lab in collaboration with colleagues from the Institute for Diabetes and Cancer and the Institute of Virology, Helmholtz Zentrum Munich as well as the Universitat Rovira i Virgili, Spain decoded the intricate changes that occur at the transcriptional, epigenetic, and metabolic levels following loss of the PK enzyme.
In their recently published study Nieborak et al. identified changes in cancer cells upon PK depletion. Notably, they discovered an upregulation of the tumor suppressor TXNIP via the binding of two transcription factors and accumulation of activating histone modifications (H3K4me3 and H3K9ac). Interestingly, cells lacking PK also exhibited changes in cellular metabolism and an increase in the levels of epigenetically relevant metabolites. One of these metabolites is glucose-6-phosphate. It is an intermediate molecule within the glycolytic pathway and can also regulate the activity of transcription factors. The research team then showed that this new regulatory PK-TXNIP axis is not just limited to cancer cell lines but is also present in other metabolically relevant cell and animal models. These results reveal how metabolites with epigenetic relevance can intricately impact the transcriptional program of cells, and in turn, affect glycolic metabolism.
The discovery described in the recent publication holds significance not only for cancer research and new therapeutical approaches, but also helps us to understand the intricate connections between metabolism and epigenetic processes.
Epigenetics is the field that explores stable changes in cell function that do not involve alterations in the DNA sequence. Through small chemical modifications, genes can be switched on or off, influencing the fate, function, and characteristics of cells with the same DNA sequence. One example of such modifications involves modification of proteins called histones, that wrap and organize the DNA into chromatin. These modifications can affect the structure and accessibility of DNA, leading to changes in gene expression.
Transcription factors are proteins that have the capacity to bind to DNA and in turn control gene expression. Therefore, they play a crucial role in development and health.
Tumor suppressors are factors that, if mis-regulated, can contribute to the harmful progression of cancer. Normally, such factors help to control balance of cell growth and division. However, mutations or changes in tumor suppressors can disrupt this balance, resulting in detrimental effects.
Pyruvate kinases (PKs) are enzymes involved in the last step of the glucose (sugar) metabolism pathway that breaks down glucose into pyruvate. This process releases energy which is further used to fuel many cellular processes and functions.
To read the full publication, please go here.