Role of Misu (NSun2) in healthy tissues and tumourigenesis

Many adult tissues are maintained by stem cells. Failure to control the generation of stem cells or the differentiation into their progeny contribute to cancer. Thus, the goal of this project is to identity key regulators and mechanisms that control the maintenance of healthy skin by regulating stem cell growth and differentiation. Once we have identified important factors regulating stem cell fate, we further investigate whether their mis-regulation contribute to cancer. These approaches are being developed and exploited to uncover novel mechanisms and pathways that are involved in cancer development and could well lead to the discovery of novel anti-cancer drug targets.

The transcription factor Myc is one of the best described proto-oncogenes, but its functions in non-malignant cells remain enigmatic. Over the last 7 years, we have shown that Myc is involved in regulating epidermal stem cell homeostasis in normal skin. The exact mechanisms of how Myc regulates stem cell fate are not very well understood. We have recently described a novel direct down-stream target of Myc, called Misu (Nsun2). Misu encodes for an RNA methyltransferase that is important for Myc-induced proliferation in primary human keratinocytes and in vitro reconstituted skin. Misu is over-expressed in many different tumours and inhibition of Misu by RNAi inhibits growth of human squamous-cell-carcinoma xenografts. However, it is still unknown whether Misu, like Myc regulates epidermal stem cell fate and how Misu regulates Myc-induced proliferation. We will now address these questions using both in vitro and in vivo approaches. We will determine whether Misu by itself regulates epidermal stem cell self-renewal and differentiation. To further illuminate the role of Misu in cancer, we will answer the question whether inhibition of Misu will prevent tumour formation using a loss-of-function mouse model. Finally, we will analyse the mechanism of how an RNA methyltransferase regulates cell proliferation by analysing the function of dominant negative mutant constructs of Misu in normal and tumour cells. In summary, we will address two main research questions in this proposal. (1) Does Misu regulate stem cell fate in normal tissues? (2) Does inhibition of Misu prevent tumour formation? Combing these two research goals is essential; only when we understand the role of Misu in normal tissue we will be able to determine how it can contribute to cancer and whether it represents a novel anti-cancer drug target.