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March 7th, 2025
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University of California Irvine
cancer biology
biorxiv

UHRF1 is critical for tumor-promoting inflammation and tumorigenesis in retinoblastoma

Gu, Y.Open in Google Scholar•Suarez-Pizarro, M.Open in Google Scholar•Chen, C. C.Open in Google Scholar•Wu, J.Open in Google Scholar•Zocchi, L.Open in Google Scholar•Suh, S.Open in Google Scholar•Smith, P. J.Open in Google Scholar•Cruz, S. M.Open in Google Scholar•Tinoco, R.Open in Google Scholar•Benavente, C. A.Open in Google Scholar

Retinoblastoma, the most common pediatric intraocular malignancy, arises from RB1 inactivation, leading to uncontrolled proliferation of retinal progenitor cells. Epigenetic dysregulation a key driver of retinoblastoma progression, yet the underlying mechanisms are poorly understood. UHRF1, a regulator of DNA methylation and chromatin remodeling, has been implicated in oncogenesis but its role in retinoblastoma has not been fully characterized. To investigate Uhrf1's role in tumor initiation and progression, we generated a genetically engineered mouse model of retinoblastoma with conditional Uhrf1 knockout. Remarkably, Uhrf1 loss completely blocked tumor formation, despite persistent early oncogenic events. Transcriptomic and epigenomic profiling revealed that Uhrf1 is essential for tumor progression, facilitating oncogenic transcription, chromatin accessibility, and aberrant DNA methylation. Beyond its epigenetic role, we found Uhrf1 modulates the tumor immune microenvironment, promoting chemokine secretion and microglial infiltration, suggesting that Uhrf1 promotes immune cell recruitment. Mechanistically, Uhrf1 enhances chemokine expression through NF-{kappa}B signaling, establishing a novel connection between epigenetic regulation and tumor-associated immune responses. These findings establish Uhrf1 as a critical driver of retinoblastoma progression, essential for tumor maintenance but not initiation. By sustaining oncogenic transcriptional programs and shaping a pro-tumor immune microenvironment, Uhrf1 emerges as a promising therapeutic target for inhibiting tumor growth and immune evasion.

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