Abstract 2985: UHRF1 drives small cell lung cancer progression and immune evasion via epigenetic regulation

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer, with a five-year survival rate of less than 8%. This poor prognosis stems primarily from rapid tumor growth, early metastasis, and an immunologically “cold” tumor microenvironment. A hallmark of SCLC is the near-universal inactivation of the RB transcriptional corepressor 1 (RB1), yet therapeutic advancements have been hindered by the lack of targetable oncogenic mutations. Our research has identified ubiquitin-like containing PHD and RING Finger domains 1 (UHRF1) as a direct downstream target of the RB pathway and a key protein overexpressed in RB-deficient cancers, including SCLC. Elevated UHRF1 expression correlates with poor survival outcomes in SCLC patients, but its specific role in disease progression remains poorly understood. We hypothesized that UHRF1 overexpression is critical for SCLC tumor progression. To test this hypothesis, we employed CRISPR-Cas9 and shRNA to disrupt UHRF1 expression in human SCLC cell lines. We assessed changes in tumor cell proliferation, clonogenicity, migration, and invasion in vitro, alongside primary tumor growth, metastasis, and survival in vivo. Additionally, we developed genetically engineered mouse models of SCLC to explore Uhrf1’s role of in tumor development, particularly its interaction with the immune microenvironment. Our findings reveal that UHRF1 overexpression drives a more aggressive tumor phenotype by promoting SCLC proliferation, angiogenesis, and maintaining an immune “cold” environment. Loss of UHRF1 in both human and mouse models led to significantly improved survival outcomes. These results underscore UHRF1’s critical role in SCLC progression and highlight its potential as therapeutic target. To elucidate the molecular mechanisms behind UHRF1’s oncogenic roles, we performed transcriptomic analysis using bulk RNA-seq, further validated by RT-qPCR. Upon UHRF1 KO, we observed significant gene expression changes, including downregulation of ST6GALNAC5 and upregulation of MAGEA4, RERG, and TGFBI. Pathway analysis suggests that UHRF1 modulates these downstream targets epigenetically, potentially through DNA methylation. In conclusion, our study identifies UHRF1 as an oncogenic driver in SCLC, facilitating tumor growth, metastasis, and immune evasion via epigenetic regulation. These findings provide a foundation for developing targeted therapies aimed at UHRF1 or its key downstream effectors to improve outcomes for SCLC patients. Citation Format: Yijun Gu, Claudia Benavente. UHRF1 drives small cell lung cancer progression and immune evasion via epigenetic regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2985.