Our research axes

The vast majority of lysine methyltransferases are still poorly characterized and for the most part their activity is unknown or not thoroughly analyzed. For example, we demonstrated that the lysine methyltransferases SMYD3 does not methylate histone H3 as previously claimed in literature, but has clear multiple oncogenic activities. Indeed, SMYD3 is a key actor of RAS-dependent lung and pancreatic adenocarcinoma progression through the methylation of the cytoplasmic kinase MAP3K2 (Mazur et al., Nature 2014). Recently, we found that SMYD3 regulates small cell lung cancer sensitivity to alkylating chemotherapy through the methylation of the E3 ligase RNF113A (Lukinovic et al., Cancer Discovery 2022). Thanks to the dynamics and fine regulation of lysine methylation, a better characterization of new oncogenic lysine methylation signaling will provide valuable alternatives for cancer treatments.

Besides a poor characterization of KMTs function in cancer, the physiologic functions of the vast majority of KMTs remain unknown. For example, while overexpression of SMYD2 and SMYD3 KMTs are clearly linked to oncogenic processes, KO mouse models for both enzymes do not harbor evident phenotypes. Therefore, we aim to identify the physiologic relevance of several KMTs, which will also allow us to identify potential functional consequences of any alteration regarding their related signaling pathways in cell homeostasis.

Lysine methylation signaling is a finely regulated post-translational modification. The discovery of lysine demethylases opened up a dynamic aspect of this signaling, for the most part restricted to methylated lysines on histone to date. However, similar to KMTs, lysine demethylases may have broader cellular impact by affecting non-histone methylated proteins. We aim to identify KDMs involved in the regulation of key methylation signaling. As KDMs may counteracts oncogenic or tumor suppressive lysine methylation signaling,  they also represent potential interesting therapeutic targets.