Abstract 2723: Unveiling epigenetic mechanisms driving RasGRP3 upregulation via oncogenic Gαq signaling in uveal melanoma

Abstract Uveal melanoma (UM) is a rare but aggressive cancer originating from melanocytes within the eye. It is distinct from cutaneous melanoma (CM) and genetically defined by somatic mutations activating the Gαq signaling pathway, most commonly affecting the Gαq subunits GNAQ or GNA11. UM remains a highly lethal melanoma subtype that cannot be effectively treated by current treatment regimens, including immune checkpoint blockade and targeted therapies. RasGRP3 (RAS Guanyl Releasing Protein 3), a guanine nucleotide exchange factor (GEF) for Ras, is markedly (>100-fold mRNA levels compared to CM) and selectively upregulated in UM and serves as a critical signaling hub connecting Gαq signaling to the MAPK pathway. Elucidating the mechanisms underlying the RasGRP3 upregulation unique for UM promises to unveil alternative therapeutic targets. We compared the epigenetic landscape of the RasGRP3 locus in UM and CM cells using ChIP-seq for H3K27ac (marking active enhancer/promoters), H3K4me1 (active enhancers), and H3K4me3 (active promoter). In UM but not CM cells, the RasGRP3 locus was highly enriched for H3K27ac and H3K4me1 modifications, and two of its three transcription start sites were marked with elevated H3K4me3 levels, indicating the expression of two major isoforms in UM. Treatment of UM cells with the Gαq inhibitor YM-254890 (YM) or the PKC inhibitor LXS-196 (LXS) for 24 hours significantly reduced all three histone modifications (H3K4me3, H3K27ac, H3K4me1) at the RasGRP3 locus. No changes were observed in CM cells. Our findings indicate an active super-enhancer that regulates RasGRP3 expression in UM, which is under control of the Gαq pathway through epigenetic modifications at its promoter and enhancer regions. These findings explain the selective upregulation RasGRP3 characteristics of UM. Ongoing investigations aim to delineate the precise mechanisms by which Gαq signaling drives these epigenetic changes. Our results highlight the potential of targeting specific histone modifiers as a novel therapeutic strategy for UM treatment. Citation Format: Zaizhou Liu, Boris Bastian, Xu Chen. Unveiling epigenetic mechanisms driving RasGRP3 upregulation via oncogenic Gαq signaling in uveal melanoma [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 2723.