DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells

We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target. Synopsis Inhibiting DiPRO1 promotes myogenesis in myoblasts yet leads to apoptosis in rhabdomyosarcoma and Ewing sarcoma cells. Targeting DiPRO1 with si/shDiPRO1 nanomedicines represent a potential treatment avenue for mesenchymal cancers. DiPRO1, in conjunction with TIF1B and UHRF1, participates in the epigenetic silencing of cellular responses to viruses by maintaining the repression of retrotransposable repeats (RE). DiPRO1 plays a role in cell fate determination as a modulator of TNF-α via NF-kappaB signaling. DiPRO1 myogenic regulatory functions extend to SIX1 binding sites. Inhibiting DiPRO1 promotes myogenesis in myoblasts yet leads to apoptosis in rhabdomyosarcoma and Ewing sarcoma cells. Targeting DiPRO1 with si/shDiPRO1 nanomedicines represent a potential treatment avenue for mesenchymal cancers.