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Modulation of Spliceosomal Proteins hnRNPH1 and H2 Increases Melanoma Cell Pro-Inflammatory Signaling In Vitro
Maab Sultan1, Shuai Ma2, Juan Diez1,3
1Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, 3321 College Avenue, Fort Lauderdale, FL 33314, USA.
Abstract:
Melanoma is the most aggressive and deadliest form of skin cancer, and the current treatments of melanoma have many limitations, which necessitate discovering new compounds and targets for melanoma. Two probes, 2155-14 and 2155-18, were identified to induce apoptotic cell death, autophagy, and immune signaling modulation through hnRNPH1/H2-dependent mechanisms. RNA sequencing following the siRNA-mediated knockdown of hnRNPH2 in melanoma cells revealed an enrichment of immune-related signaling pathways. The present study investigated the effect of genetic and pharmacologic downregulation of hnRNPH1/H2 on melanoma immunogenicity in vitro. Our results indicated that treating melanoma cell lines with 2155-14 and 2155-18 led to hnRNPH1/H2 downregulation, whereas hnRNPH2 siRNA treatment led to only hnRNPH2 downregulation. Both types of treatment resulted in a significant upregulation of pro-inflammatory pathways and simultaneous downregulation of anti-inflammatory pathways. 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.
Insights
New compounds 2155-14 and 2155-18 target hnRNPH1/H2, modulating melanoma cell immunity. This research reveals hnRNPH1/H2 as key drivers of melanoma immunogenicity, offering potential new therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Melanoma is an aggressive skin cancer with limited treatment options.
- hnRNPH1/H2 proteins play a role in cellular processes relevant to cancer.
- Modulating the tumor immune microenvironment is a promising therapeutic strategy.
Purpose of the Study:
- To investigate the effect of hnRNPH1/H2 downregulation on melanoma immunogenicity.
- To explore novel therapeutic targets for melanoma treatment.
Main Methods:
- Utilized RNA sequencing after siRNA-mediated knockdown of hnRNPH2.
- Treated melanoma cell lines with probes 2155-14 and 2155-18.
- Assessed changes in pro-inflammatory and anti-inflammatory pathways.
Main Results:
- Probes 2155-14 and 2155-18 downregulated hnRNPH1/H2.
- hnRNPH2 siRNA specifically downregulated hnRNPH2.
- Both treatments upregulated pro-inflammatory and downregulated anti-inflammatory pathways.
Conclusions:
- hnRNPH1/H2 are critical regulators of melanoma immunogenicity.
- Targeting hnRNPH1/H2 offers a potential strategy for enhancing melanoma immunotherapy.
- Post-transcriptional regulation significantly impacts the melanoma immune microenvironment.
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