Saudi Cultural Missions Theses & Dissertations
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Item Restricted The Role of hnRNPH1 and H2 in Melanoma Immune Signaling(Saudi Digital Library, 2025) Sultan, Maab Khalid; Dmitriy, MinondMelanoma is the most aggressive and deadliest form of skin cancer, responsible for an estimated 58,667 deaths globally, accounting for 0.6% of all cancer-related mortality. Current treatments for melanoma include chemotherapy, immunotherapy, and targeted therapy; however, challenges such as drug resistance, low response rates, and limited options for triple-wild type (TWT) and NRAS mutant melanoma persist. Melanoma is mainly controlled by the Ras/Raf/MEK/ERK pathway, and its tumors typically contain a high number of genetic mutations, making treatment difficult with existing therapies. However, this high mutation burden could also increase melanoma’s responsiveness to immunotherapy. Previous studies have shown that spliceosomal proteins hnRNPH1/H2 support the progression and survival of various cancers; however, their role in melanoma remains unexplored. hnRNPs, RNA-binding proteins, play a critical role in regulating alternative splicing, and modulating this process with small-molecule probes could help overcome resistance to immunotherapy. Two such probes, 2155-14 and 2155-18, were identified to induce apoptotic cell death, autophagy, and immune signaling modulation, with effects mediated through hnRNPH1/H2-dependent mechanisms. RNA sequencing following the downregulation of hnRNPH1/H2 in melanoma cells revealed an enrichment of immune-related signaling pathways. A recent study also linked increased immune-related pathways with improved overall survival in melanoma patients. The present study investigated the effect of genetic and pharmacologic downregulation of hnRNPH1/H2 on melanoma immunogenicity in vitro. Furthermore, it explored how pharmacological modulation of these proteins contributes to the regulation of melanoma immunogenicity using a syngeneic melanoma mouse model. Our results indicate that both genetic and pharmacologic downregulation of hnRNPH1/H2 significantly upregulated pro-inflammatory pathways while downregulating anti-inflammatory pathways. In vivo studies showed that 2155-18 had a stronger effect than 2155-14. Compound 2155-18 increased the population of active CD8+ T cells without affecting immunosuppressive cell populations, including Tregs, MDSCs, and mMDSCs. These findings provide the first insight into the role of hnRNPH1/H2 as critical drivers of melanoma immunogenicity and suggest their potential as novel therapeutic targets for enhancing melanoma treatment outcomes. This study underscores the impact of post-transcriptional regulation on the immune environment in melanoma and in cancer in general.13 0