VAV2-DEPENDENT REGULATION OF RIBOSOME BIOGENESIS IN KERATINOCYTES AND ORAL SQUAMOUS CELL CARCINOMA

Abstract

VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (oSCC) cells, respectively. Here, we demonstrate that VAV2 also plays critical roles in the regulation of ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus negative oSCC patients. Mechanistic analyses indicate that VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway composed of the GTPases RAC1 and RHOA, members of the PAK and ROCK family kinases, and the transcriptional factors c-MYC and YAP/TAZ. This pathway directly promotes RNA polymerase I activity and the ensuing synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent cell undifferentiation state. Finally, we show that RNA polymerase I is a therapeutic Achilles heel for both keratinocytes and hnSCC patient derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of the VAV2 and ribosome biogenesis pathways in both preneoplastic and late progression stages of oSCC.