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

RICH, J.; BENNAROCH, M.; NOTEL, L.; PATALAKH, P.; ALBEROLA, J.; OPOLON, P.; BAWA, O.; RONDOF, W.; MARCHAIS, A.; DESSEN, P.; MEURICE, G.; POLROT, M.; SER-LE ROUX, K.; DROIN, N.; RASLOVA, H.; GEOERGER, B.; PIROZHKOVA, I. V.

doi:10.1101/2023.01.08.523169

bioRxiv · 10.1101/2023.01.08.523169

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

RICH, J.·BENNAROCH, M.·NOTEL, L.·PATALAKH, P.·ALBEROLA, J.·OPOLON, P.·BAWA, O.·RONDOF, W.·MARCHAIS, A.·DESSEN, P.·MEURICE, G.·POLROT, M.·SER-LE ROUX, K.·DROIN, N.·RASLOVA, H.·GEOERGER, B.·PIROZHKOVA, I. V.

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Abstract

We 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- 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 O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/523169v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@146f1e5org.highwire.dtl.DTLVardef@b3265borg.highwire.dtl.DTLVardef@19b52fcorg.highwire.dtl.DTLVardef@654f6d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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RICH, J., BENNAROCH, M., NOTEL, L., PATALAKH, P., ALBEROLA, J., OPOLON, P., BAWA, O., RONDOF, W., MARCHAIS, A., DESSEN, P., MEURICE, G., POLROT, M., SER-LE ROUX, K., DROIN, N., RASLOVA, H., GEOERGER, B., PIROZHKOVA, I. V.. 2023-01-08. DiPRO1 dependent transcriptional and epigenetic regulation distinctly controls the fate of muscle and mesenchymal cancer cells.. https://doi.org/10.1101/2023.01.08.523169

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