Abstract Mesothelioma is a highly aggressive malignancy of the serosal membranes. Alterations in regulatory mechanisms controlling tumor suppressor gene expression play a critical role in Mesothelioma and other malignancies. Although tumor suppressor genes are central to cancer biology, the upstream regulation networks governing their activity remain poorly defined. Here, we identify a novel molecular pathway that directly regulates BAP1 tumor suppressor gene transcription and drives oncogenic p