DiPRO1 dependent transcriptional and epigenetic regulation distinctly controls the fate of muscle and mesenchymal cancer cells

Abstract

ABSTRACTWe have recently identified the uncharacterized ZNF555 protein as a component of a productive complex, which is involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. As a result of our current findings, ZNF555 is hereinafter referred to as DiPRO1 (Death, Differentiation and PROliferation related PROtein 1). In this study, we provide substantial evidence that DiPRO1 plays a role in human myoblast differentiation. It acts on regulatory binding regions of SIX1, which is a master regulator of myogenesis. We further describe the relevance of DiPRO1 in mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma. DiPRO1 plays a repressor role in these tumors via the epigenetic regulators TIF1B and UHRF1 in order to maintain methylation of regulatory cis-elements and promoters. Loss of DiPRO1 eradicates cancer cells, by switching on a distinct transcriptional and epigenetic program. It consists of mimicking the host defense against the virus response by awakening the retrotransposable repeats (RE) and the ZNP/KZFP gene family. DiPRO1 also contributes to the balance of cellular decisions toward inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, we demonstrate that mesenchymal cancer tumors are vulnerable in response to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential new target for therapeutic intervention.Summary