ZNF16 is a nucleolar-associated protein that regulates expression of the rDNA and cancer-associated genes

George, C. L.; Quevedo, L. A. E.; Paratore, J.; Alcaraz, M. J.; Levario, A. P.; Rahmatallah, Y.; Glazko, G. V.; Reyna, N. S.; Diaz-Martinez, L. A.

doi:10.1101/2025.10.16.682606

bioRxiv · 10.1101/2025.10.16.682606

ZNF16 is a nucleolar-associated protein that regulates expression of the rDNA and cancer-associated genes

George, C. L.·Quevedo, L. A. E.·Paratore, J.·Alcaraz, M. J.·Levario, A. P.·Rahmatallah, Y.·Glazko, G. V.·Reyna, N. S.·Diaz-Martinez, L. A.

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Abstract

ZNF16 (also known as HZF1 and KOX9) is a multi-C2H2 zinc finger protein first identified via its expression in human T-cells and shown to have a role in blood cell differentiation. ZNF16 was later shown to be ubiquitously expressed in a variety of fetal and adult tissues, suggesting a broader function. In this study, we confirm the ubiquitous expression of ZNF16 in a variety of cancer and non-cancer cell lines and show that ZNF16 depletion reduces cell viability in all cell lines tested. Furthermore, we show that ZNF16 localizes to the nucleolus in a transcription-dependent manner, interacts with the intergenic spacer region of the rDNA and promotes rDNA transcription. Additionally, RNA-seq experiments after ZNF16 depletion revealed that ZNF16 also has roles in a variety of pathways including ECM-receptor interaction, focal adhesions, cytokine-cytokine receptor interactions, human papillomavirus (HPV) infection and cancer pathways. These findings are consistent with broader roles for ZNF16, including the regulation of nucleolar function, a process that is essential for all cells, and provide evidence at the cellular/molecular level of its role in the regulation of cancer-associated genes (e.g., NRAS, BIRC3, EGFR).

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George, C. L., Quevedo, L. A. E., Paratore, J., Alcaraz, M. J., Levario, A. P., Rahmatallah, Y., Glazko, G. V., Reyna, N. S., Diaz-Martinez, L. A.. 2025-10-17. ZNF16 is a nucleolar-associated protein that regulates expression of the rDNA and cancer-associated genes. https://doi.org/10.1101/2025.10.16.682606

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