The m6A hypermethylation-induced PIR overexpression regulates H3K4me3 and promotes tumorigenesis of uveal melanoma

Uveal melanoma (UM) is the most common primary ocular malignancy in adults, characterized by high mortality, strong metastatic potential, and limited treatment options, necessitating the identification of novel therapeutic targets. Here, we identified Pirin (PIR) as a key oncogenic factor in UM through comprehensive multi-omics analyses, revealing that PIR is significantly upregulated and correlates with poor prognosis. Functional assays indicated that inhibiting PIR markedly suppressed UM progression, highlighting its critical role in tumorigenesis behavior. Mechanistically, PIR expression is driven by aberrant N6-methyladenosine (m⁶A) modifications mediated by METTL3 and IGF2BP3. Meanwhile, the high expressed PIR acts as a transcriptional co-regulator by interacting with WDR5, resulting in the regulation of H3K4me3 modifications at the ANAPC10 promoter region and subsequent promotion of ANAPC10 expression. Overall, our study uncovered the METTL3/IGF2BP3 (m6A)-PIR-WDR5 (H3K4me3)-ANAPC10 axis, bridging RNA methylation and histone methylation in UM pathogenesis. By unmasking these intricate epigenetic interactions, we provided novel insights into UM biology and identified potential therapeutic targets for tumor treatment, offering the theoretical support for future drug development and clinical applications.