VRK1 regulates epigenetic chromatin modifications and its implication for novel cancer therapies

Resumen del trabajo presentado en el Congreso "Cancer Epigenetics: Principles, applications and single-cell resolution", celebrado en Spetses (Grecia) del 28 de agosto al 03 de septiembre de 2022.Epigenetic regulation of gene expression and DNA damage responses are mediated by chromatin remodeling, which involves histone post-translational modifications (PTMs). These PTMs result in dynamic shifts between different degrees of chromatin compaction. Thus, it is crucial to unveil the molecular mechanisms that modulate these changes and the histone-modifying enzymes involved in such regulation. VRK1 (Vaccinia-related kinase 1) is a nuclear/chromatin kinase implicated in different cellular processes like transcription or DNA damage response. In this context, we studied the potential role of VRK1 in the regulation of these epigenetic modifiers. In our study, we evaluated the levels of different PTMs in two human cancer cell lines, A549 (lung adenocarcinoma) and U2OS (osteosarcoma). We next compared the effect of VRK1 silencing with the effect of inhibitors of several epigenetic enzymes. Finally, we studied the potential interaction of VRK1 with specific epigenetic modifiers. Our results showed that VRK1 knock-down induced an alteration of histone PTMs. We observed that VRK1 depletion promotes a decrease in H3K4me3, H3K9ac, H3K27ac, and H4K16ac levels and an increase in H3K9me3 and H3K27me3. Moreover, VRK1 absence mimics the effect of HATi (C646 and MG149) and KDMi (JMJD2i and ORY-1001), while the presence of VRK1 mimics the effect of HDACi (Vorinostat, Entinostat, Panobinostat, Selisistat, Thiomyristoil, AGK2, and AK7) and KMTi (Chaetocin and Tazemetostat). Furthermore, VRK1 forms a stable protein complex with KDM1a, KDM3a, KDM4a, HDAC1, SIRT1/2, and SETDB1. Our findings revealed that permissive chromatin marks (H3K4me3, H3K9ac, H3K27ac, H4K16ac) decreased while repressive marks (H3K9me3, H3K27me3) increased in VRK1-depleted cells. Therefore, the loss of VRK1 expression had the same effect as the inhibition of the epigenetic enzymes that interact with VRK1, suggesting that VRK1 might be a regulator of them and used as potential target for novel cancer therapies