Currently, we have two major themes in the laboratory:
1. Explain the functional relevance of OGT in the control of transcription
2. Target transcriptional kinases as cancer-therapy
O-GlcNAc transferase (OGT) is an essential factor in the higher eukaryotes and the enzyme carries out all the nucleocytoplasmic glycosylation. OGT attaches a single sugar unit on the target proteins’ serine and threonine aminoacids, and thereby competes with the kinases for the substrate availability. OGT is overexpressed in most cancers and depletion of its activity halts proliferation of these cells.
OGT was linked to transcriptional regulation in early 90’s, when it was discovered that the enzyme responsible for the expression of the protein-encoding genes, RNA Pol II, is glycosylated. Subsequently, the repertoire of OGT substrates has been vastly expanded, and OGT is known to play a role in both transcriptional repression and activation. At the moment, the lack of tools to selectively enrich a specific glycosylated protein has halted the understanding of how this modification affects protein function. In collaboration with the University of Turku, we are developing glyco-specific antibodies using the phage display system.
To better understand how OGT activity is altered in response to depleting the activity of a specific transcriptional kinase, we have used glycoproteomics. These experiments are shedding light on how OGT acts as a context-dependent regulator of transcription. Interestingly, many of the gained OGT substrates appear to form synthetic lethal pairs with existing therapies.
Our second major focus is to target transcriptional kinases as cancer therapy. It is striking that compounds specifically inhibiting these kinases are well tolerated by the normal cells, while cancer cells are addicted on their high activity, as revealed by the successful clinical trials.
Our hypothesis is that the acquired anomalies of the cancer cells render them reliant on the high activity of the transcriptional kinases. In order to test this hypothesis, we have established a panel of models that represent both normal and cancer cells, and are assessing which of these models are particularly addicted on the high activity of a specific kinase. In parallel, we perform comprehensive transcriptional profiling (alternative splicing, metabolic labeling of RNA along with the traditional RNA-seq), to establish how the cancer cells most susceptible against a given inhibitor rewires their transcriptional program.