Fig 2: Possible molecular targets involved in the occurrence and development of uveal melanoma are screened by bioinformatics analysis.AThe heatmap for differential gene expression in GSE113625 uveal melanoma dataset. X-axis represents sample number, Y-axis represents gene name, left dendrogram represents gene expression clustering, each small block in the figure represents the expression of a gene in a sample, and the upper right histogram is color scale. B KEGG pathway enrichment analysis of differentially expressed genes. X-axis represents GeneRatio, the Y-axis represents KEGG entry, the circle color represents the corrected enrichment p value, the size represents the number of genes enriched in the entry, and the right histogram is the color scale. C IL5RA upstream transcription factor prediction. Two circles in the figure represent the prediction results of JASPAR database and hTFtarget database, and the middle part represents the intersection of the two groups of data. D The expression of TP53, YY1, MEF2A, STAT3, and NR3C1 in uveal melanoma (n = 32) and normal controls (n = 30) determined by RT-qPCR. * p < 0.05. E Correlation analysis between TP53 and MDM2 mRNA expression in the uveal melanoma samples from TCGA database. The abscissa represents the expression value of MDM2, the ordinate represents the expression value of p53, and the p value the correlation and the Pearson’s correlation coefficient are presented in the top. F Correlation analysis between JMJD2C (KMD4C) and MDM2 mRNA expression in the uveal melanoma samples from TCGA database. X-axis represents JMJD2C expression value, Y-axis represents MDM2 expression value, and the p value for the correlation and Pearson’s correlation coefficient are presented in the top.

Fig 3: MDM2 degrades p53 through ubiquitination and promotes the expression of IL5RA.A The expression of p53 in normal uveal epithelial cells ARPE-19, uveal melanoma cells MUM-2B, and drug-resistant cell line MUM-2B/CDDP as determined by RT-qPCR. B The expression of p53 in MUM-2B/CDDP cells upon JMJD2C silencing and MUM-2B cells upon JMJD2C overexpression as measured by Western blot assay. C The expression of p53 in MUM-2B cells upon MDM2 overexpression as measured by Western blot assay. D The stability of p53 protein after CHX treatment. E The expression of IL5RA in uveal melanoma tissues as determined by RT-qPCR (uveal melanoma = 32, normal = 30). F The expression of IL5RA in normal uveal epithelial cells ARPE-19, uveal melanoma cells MUM-2B and drug-resistant cell line MUM-2B/CDDP as determined by RT-qPCR. G IL5RA expression in MUM-2B/CDDP cells upon p53 overexpression and MUM-2B cells upon p53 silencing measured by Western blot assay. H The enrichment of p53 in the IL5RA promoter region in MUM-2B/CDDP cells and MUM-2B cells analyzed by ChIP. I The expression of MDM2, p53, and IL5RA in MUM-2B cells treated with oe-MDM2 or combined with oe-p53 as measured by Western blot assay. * p < 0.05. Cell experiments were repeated three times independently.

Fig 4: JMJD2C accelerates the growth of uveal melanoma and increases CDDP resistance in nude mice via regulation of the MDM2/p53/IL5RA axis.A The expression of JMJD2C, MDM2, p53, and IL5RA in tumors derived from MUM-2B cells and MUM-2B/CDDP cells as measured by Western blot assay. B Representative images showing xenografted tumors in derived from MUM-2B cells and MUM-2B/CDDP cells and tumor growth curves. C The statistical plot for tumor weight of MUM-2B- and MUM-2B/CDDP-implanted nude mice. D Positive rates of Ki67 and PCNA in MUM-2B cell- and MUM-2B/CDDP cell-derived tumor tissues of nude mice as detected by immunohistochemistry. Scale bar = 50 µm. n = 8 for mice following each treatment. * p < 0.05.

Fig 5: The molecular mechanism by which JMJD2C affects CDDP resistance in uveal melanoma.JMJD2C promotes the expression of MDM2 by removing the H3K9me3 modification of the MDM2 promoter, thus promoting the ubiquitination and degradation of p53, increasing the expression of IL5RA, and ultimately promoting CDDP resistance in uveal melanoma.