NUDT21-mediated Alternative Polyadenylation of CDK19 Reprograms Cholesterol Biosynthesis to Drive Colorectal Cancer

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Published on: September 26, 2019

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Yeping Yu1, Jixin Ma1, Minwei Zhou1

  • 1Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 19, 2025
PubMed

Insights

Alternative polyadenylation (APA) regulator NUDT21 drives colorectal cancer (CRC) by altering cholesterol metabolism and immune evasion. Depleting NUDT21 impairs tumor growth and enhances anti-tumor T cell responses in CRC.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Alternative polyadenylation (APA) generates mRNA variants impacting gene expression.
  • APA dysregulation is implicated in cancer, but its role in colorectal cancer (CRC) is unclear.
  • NUDT21 is identified as a potential regulator of APA in CRC.

Purpose of the Study:

  • To investigate the role of NUDT21 in colorectal cancer (CRC) progression.
  • To elucidate the molecular mechanisms by which NUDT21 influences CRC.
  • To explore the therapeutic potential of targeting the NUDT21-CDK19 axis in CRC.

Main Methods:

  • CRISPR/Cas9 screening to identify APA regulators in CRC.
  • NUDT21 expression analysis in CRC tumors and correlation with patient prognosis.
  • Genetic ablation of NUDT21 in CRC cells and mouse models.
  • Analysis of NUDT21's impact on cholesterol biosynthesis and CD8+ T cell response.
  • Investigation of NUDT21's role in regulating CDK19 mRNA polyadenylation and translation.

Main Results:

  • NUDT21 is overexpressed in CRC and associated with poor prognosis.
  • NUDT21 depletion inhibits CRC cell proliferation and enhances CD8+ T cell anti-tumor immunity.
  • NUDT21 promotes long 3'UTR isoforms of CDK19, facilitating its translation.
  • CDK19's 3'UTR length is crucial for cholesterol biosynthesis and proliferation.
  • Restoring CDK19 expression rescues phenotypes observed upon NUDT21 depletion.

Conclusions:

  • The NUDT21-CDK19 axis is a key regulator of cholesterol metabolism and immune evasion in CRC.
  • NUDT21 drives CRC progression by modulating APA of CDK19.
  • Targeting NUDT21 or CDK19 may offer novel therapeutic strategies for CRC.
Keywords:
CDK19NUDT21alternative polyadenylationcholesterol biosynthesiscolorectal cancer

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