NUDT21 (Nudix Hydrolase 21)

This study underscores the pivotal contribution of RNA splicing in BCa metastasis, with SNW1 serving as a key mediator. The identification of key regulatory molecules provides valuable insights into potential therapeutic targets for clinical intervention in metastatic BCa.

Truncation of the long 3'UTR of Cdk19 recapitulates cholesterol biosynthesis and proliferative impairments, as well as the enhanced anti-tumor CD8+ T cell activity observed upon NUDT21 depletion, whereas CDK19 overexpression rescues these phenotypes. The findings establish the NUDT21-CDK19 axis as a central hub integrating APA manner, cholesterol metabolic reprogramming, and immune evasion in CRC, unveiling potential therapeutic opportunities.

Blocking the AKT2 proximal polyadenylation site usage causes a decrease in Akt2 protein, suppressing M1 polarization phenotypes including NOS activity and cytokine profiles. The CFIm25-Akt2-NF-κB axis represents a novel target for macrophage polarization reprogramming.

Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.

Subsequently, we illustrate that the long isoform inhibits tumor growth and metastasis by binding to CDK1 and blocking the G2/M phase of the cell cycle. In conclusion, this study uncovers a previously unrecognized regulatory mechanism in OC, which could provide potential therapeutic strategies for OC.

Mechanistically, rs9606 induces aberrant APA process of LYRM4 via allele-specific interacting with NUDT21, which lead to increased expression of oncogene LYRM4 and thus contribute to NSCLC risk. This study demonstrates the distinct contribution of APA-associated genetic variants in NSCLC risk, providing critical clues and potential targets for NSCLC etiology and clinical intervention.

Use of miRNA mimics and inhibitors showed that miR-23a, miR-222, and miR-323a play a significant role in regulating NUDT21 expression. Hence, these results suggest that NUDT21 mRNA is stable and the different 3'UTRs generated through APA of NUDT21 play an important role in evading miRNA regulation and offers insights into how levels of CFIm25 (NUDT21) may be fine-tuned as needed under different physiological and pathological conditions.

The un-methylation of NUDT21-mediated 3'UTR shortening unveils a novel mechanism for enzalutamide resistance, and our findings offer innovative strategies for advancing the treatment of prostate cancer patients experiencing enzalutamide resistance.

In particular, overexpression of miR-23, miR-24, and miR-27 in U251 cells resulted in CFIm25 downregulation at both the mRNA and protein levels, while their inhibition increased CFIm25 and reduced cell proliferation. These observations strongly implicate miR-23, miR-24, and miR-27 in regulating CFIm25 expression in GBM, emphasizing their potential as promising therapeutic targets for enhancing treatment responses in glioblastoma.

Furthermore, we constructed a nomogram to interpret the clinical application of the 4-DRRGs signature. In conclusion, we identified a prognostic signature based on the DRRGs for patients with EC, which can contribute independent value in identifying clinical outcomes that complement the TNM system in EC.

In summary, our study unraveled abnormalities in m6A regulator expression in PCa progression, elucidating their association with PCa risk loci. Considering the heterogeneity within the PCa phenotypes and treatment responses, our findings suggest that prognostic stratification based on m6A regulator expression could enhance PCa diagnosis and prognosis.

Further functional characterization using the CRISPR-Cas13d system demonstrated that circBARD1, overexpressed in TCF3::PBX1 patients and regulated by NUDT21, might be involved in leukemogenesis through the activation of p38 via hsa-miR-153-5p. Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL.