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Background <p>Wnt signaling is a key driver of colorectal cancer (CRC) progression, yet directly inhibiting it remains a major challenge. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression, thereby modulating oncogenic pathways. However, the role of miR-27a-5p and its underlying mechanisms in CRC remains largely unknown.</p> Methods <p>Bioinformatics analyses and paired clinical CRC specimens were used to evaluate miR-27a-5p expression levels and their association with prognosis. CCK-8, colony formation, wound healing, Transwell invasion, and epithelial–mesenchymal transition (EMT) marker analysis were performed to assess the effects of miR-27a-5p on the malignancy of CRC cells. The potential underlying mechanisms were investigated using dual-luciferase reporter assays, RNA-seq, HPLC-UV, immunoprecipitation/co-immunoprecipitation and immunofluorescence. Xenograft models were used to evaluate the in vivo role of miR-27a-5p in CRC.</p> Results <p>miR-27a-5p was downregulated in CRC, and its low expression correlated with poorer prognosis. miR-27a-5p directly targeted GFPT2, the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), thereby decreasing intracellular uridine 5′-diphosphate N-acetyl-D-glucosamine (UDP-GlcNAc) levels and global protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation), which in turn reduced β-catenin O-GlcNAcylation, inhibited its nuclear accumulation, and suppressed its transcriptional activity, leading to attenuation of Wnt signaling. Restoring miR-27a-5p expression in CRC cells suppressed proliferation, migration, invasion, and EMT, whereas GFPT2 overexpression or glucosamine supplementation partially reversed the inhibited malignant behaviors. Conversely, β-catenin knockdown attenuated the malignant phenotypes and expression of EMT/Wnt targets induced by miR-27a-5p inhibition, supporting a β-catenin-dependent mechanism. In mouse xenografts, treatment with the O-GlcNAc transferase (OGT) inhibitor OSMI-1 attenuated the accelerated tumor growth driven by miR-27a-5p inhibition, supporting an O-GlcNAcylation-dependent mechanism in vivo.</p> Conclusion <p>These findings reveal a novel miR-27a-5p–GFPT2–HBP axis that links metabolic reprogramming to Wnt signaling in CRC by suppressing β-catenin activity through the reduction of UDP-GlcNAc-dependent O-GlcNAcylation, thereby restraining CRC progression. This suggests that targeting this axis could attenuate Wnt signaling and slow CRC progression.</p> Graphical Abstract <p></p>

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Attenuation of Wnt signaling by miR-27a-5p–GFPT2–HBP axis via metabolic reprogramming in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月3日

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  • Jiantao Jiang,
  • Hongxin He,
  • Xiaopeng Wang,
  • Shangkun Jin,
  • Wenmin Xiao,
  • Yun Xie,
  • Enhao Wei,
  • Chenxin Qian,
  • Jing Fu,
  • Jianmin Wang,
  • Chunkang Yang,
  • Ruirong Lin

摘要

Background

Wnt signaling is a key driver of colorectal cancer (CRC) progression, yet directly inhibiting it remains a major challenge. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression, thereby modulating oncogenic pathways. However, the role of miR-27a-5p and its underlying mechanisms in CRC remains largely unknown.

Methods

Bioinformatics analyses and paired clinical CRC specimens were used to evaluate miR-27a-5p expression levels and their association with prognosis. CCK-8, colony formation, wound healing, Transwell invasion, and epithelial–mesenchymal transition (EMT) marker analysis were performed to assess the effects of miR-27a-5p on the malignancy of CRC cells. The potential underlying mechanisms were investigated using dual-luciferase reporter assays, RNA-seq, HPLC-UV, immunoprecipitation/co-immunoprecipitation and immunofluorescence. Xenograft models were used to evaluate the in vivo role of miR-27a-5p in CRC.

Results

miR-27a-5p was downregulated in CRC, and its low expression correlated with poorer prognosis. miR-27a-5p directly targeted GFPT2, the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), thereby decreasing intracellular uridine 5′-diphosphate N-acetyl-D-glucosamine (UDP-GlcNAc) levels and global protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation), which in turn reduced β-catenin O-GlcNAcylation, inhibited its nuclear accumulation, and suppressed its transcriptional activity, leading to attenuation of Wnt signaling. Restoring miR-27a-5p expression in CRC cells suppressed proliferation, migration, invasion, and EMT, whereas GFPT2 overexpression or glucosamine supplementation partially reversed the inhibited malignant behaviors. Conversely, β-catenin knockdown attenuated the malignant phenotypes and expression of EMT/Wnt targets induced by miR-27a-5p inhibition, supporting a β-catenin-dependent mechanism. In mouse xenografts, treatment with the O-GlcNAc transferase (OGT) inhibitor OSMI-1 attenuated the accelerated tumor growth driven by miR-27a-5p inhibition, supporting an O-GlcNAcylation-dependent mechanism in vivo.

Conclusion

These findings reveal a novel miR-27a-5p–GFPT2–HBP axis that links metabolic reprogramming to Wnt signaling in CRC by suppressing β-catenin activity through the reduction of UDP-GlcNAc-dependent O-GlcNAcylation, thereby restraining CRC progression. This suggests that targeting this axis could attenuate Wnt signaling and slow CRC progression.

Graphical Abstract