A groundbreaking study titled "Unveiling the Clinical Significance of RNA Pseudouridine in Colorectal Cancer" was recently published online in Science China Life Sciences by a research team led by Professor Xiaocheng Weng, Associate Researcher Yafen Wang, Postdoctoral Fellow Shaoqing Han from Wuhan University's College of Chemistry and Molecular Sciences, and Professor Hongling Wang from Zhongnan Hospital of Wuhan University. The study systematically analyzed Ψ modification levels in key oncogenes associated with CRC, revealing significantly elevated Ψ modifications in CRC patients compared to healthy controls. These modifications correlated strongly with multiple clinical indicators, including AFP and CA125. Notably, Ψ levels in peripheral blood showed partial consistency with tumor tissues, highlighting their potential for non-invasive diagnosis.
DKC1, a core member of the pseudouridine synthase (PUS) family, catalyzes Ψ modifications in RNA, playing a critical role in post-transcriptional regulation. Previous research reported that DKC1 is markedly overexpressed in CRC tissues, where it binds to the 3'UTR of ribosomal protein mRNAs, enhancing their stability and half-life to promote malignant proliferation. Pyrazofurin, a DKC1-specific inhibitor, suppresses Ψ synthase activity, reduces ribosomal protein expression, and significantly inhibits tumor growth in xenograft models. However, the clinical relevance of other PUS family members (e.g., PUS7, PUS10) and the diagnostic or therapeutic potential of specific Ψ sites in oncogenes remain unexplored.
Utilizing cutting-edge RNA pseudouridine sequencing technologies (BID-seq/PRAISE-seq), the team profiled Ψ modifications in CRC tissues, adjacent normal tissues, and patient blood samples. The results demonstrated distinct Ψ modification patterns in CRC, with overall levels strongly correlated with the expression of DKC1, PUS7L, and PUS10, implicating these genes as key regulators of Ψ dynamics in CRC. Genome-wide Ψ profiling revealed multiple hypermodified oncogenic loci in CRC, with ribosomal protein RPL19 exhibiting coordinated upregulation at both transcriptional and Ψ levels. Comparative analysis revealed that differential Ψ modifications in tumor tissues aligned closely with clinical markers such as CA125, CA153, and CA199, while blood-based Ψ sites correlated with routine indicators like WBC and AFP. Additionally, Ψ modifications in snoRNAs emerged as potential novel tumor identifiers.
These findings not only elucidate the biological significance of RNA pseudouridine modifications in CRC but also provide a molecular framework for RNA epigenetics-based stratification and targeted interventions, paving the way for innovative diagnostic and therapeutic strategies.
