CPSF6 (Cleavage And Polyadenylation Specific Factor 6)

In vivo, RHART significantly suppressed tumor growth and expression of CPSF6, MCT4, PCNA, and PKM2, while enhancing cleaved caspase-3. These findings provide scientific evidence that RHART induces apoptotic and metabolic reprogramming effects in hepatocellular carcinoma by targeting the CPSF6/MCT4/c-Myc signaling axis, underscoring its potential as a novel natural therapeutic candidate for liver cancer.

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.

Together, the present study demonstrated for the first time that intronic polyadenylation could regulate cellular senescence, largely extending our understanding of the biological roles of intronic polyadenylation. The online version contains supplementary material available at 10.1007/s43657-024-00198-2.

Apart from the canonical chromosome 7 gain and chromosome 10q loss, we observed MDM2 gene amplification and possible rearrangements on chromosome 12 and 18 with the typical aspect of chromothripsis, harbouring two putative new gene fusions: CPSF6::CPM and PTPRR::RAB3IP. We described two patients with peculiar tumour molecular profile, widening the scenario of clinical and molecular variability in such patients.

The interaction between m6A and APA is mediated by the m6A regulator IGF2BP2 and the APA factor CPSF6. The transcripts harboring m6A modification tend to use the proximal polyadenylation signal (PAS) in ovarian cancer (OC). PUM2 promotes the malignant progression of OC through its m6A methylation and APA processing.

This study establishes a four-gene survival signature for esophageal cancer that distinguishes high-risk from low-risk populations, providing novel prognostic indicators. Immune response pathways were downregulated in high-risk patients, offering potential targets for understanding esophageal cancer mechanisms and developing immunotherapeutic strategies.

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.

The observed upregulation of CPSFs in HCC, coupled with their association with poor clinical outcomes and immune system activation, highlights their potential as prognostic indicators. Nonetheless, additional experimental studies are needed to fully elucidate the molecular mechanisms and clinical significance of CPSFs in HCC.

Xenograft experiments showed that CPSF6 knockdown suppressed tumor growth and glycolysis. Thus, CPSF6 is identified as a mediator of oxaliplatin resistance in CRC, regulated by the METTL3/m6A axis, suggesting potential therapeutic targets to overcome resistance.

Furthermore, HDAC inhibitors effectively suppress CR-driven leukemia in vitro and in vivo. Hence, our data reveals the molecular bases of oncogenic CR fusion and provides a potential therapeutic approach against AML with CR fusion.

Circ_0000673 inhibition reduced CPSF6 expression by targeting miR-548b-3p, thereby blocking proliferation, migration and invasion of CRC tumor cells.

Furthermore, c-Myc degradation by CPSF6 depletion was disturbed by FBW7 depletion or treatment with the proteasomal inhibitor MG132. Consistently, immunohistochemistry showed that CPSF6 depletion reduced the growth of Hep3B cells in BALB/c mice in orthotopic and xenograft tumor models by inhibiting tumor microenvironment-associated proteins. Overall, these findings suggest that CPSF6 enhances the Warburg effect for immune escape and angiogenesis, leading to cancer progression via c-Myc, mediated by the HK, PD-L1, and VEGF networks, with synergistic potential with sorafenib as a molecular target for liver cancer therapy.