Genetic alterations, such as mutations or translocations, in genes encoding transcriptional regulators are often encountered in human cancer and are thought to cause aberrant gene expression profiles that maintain a cancerous state. While transcription factor complexes were traditionally deemed “undruggable”, it has recently been recognized that some transcriptional – or epigenetic – regulators are indeed interesting potential drug targets for cancer treatment, among these histone methyltransferases and histone demethylases. Cancer-specific gain-of-function alterations that result in dependence on such epigenetic enzymes have mainly been found in hematological malignancies. As an example, rearrangements of the MLL gene in a subset of acute leukemias result in fusion proteins that critically depend on the histone methyltransferase Dot1L as a co-factor. Loss-of-function mutations affecting epigenetic regulators are more broadly observed across cancer types.
In our group we are utilizing RNAi, CRISPR, low molecular weight inhibitor-based screening approaches, and genomic techniques such as chromatin immunoprecipitation and next-generation sequencing in order to identify novel epigenetic regulators that are specifically required for cancer growth and survival. Furthermore, we strive to elucidate the molecular mechanisms leading to dependence on such epigenetic enzymes in different cancer settings. In our current work we are using deep-coverage shRNA pools to screen for new targets in leukemias and lymphomas as well as to characterize the mechanism of oncogenesis for epigenetic regulators with a well-established role in cancer.