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USP6NL knockdown suppresses colorectal cancer progression by inducing CASP9-Mediated apoptosis and disrupting FOXC2/SNAI1-Driven EMT and angiogenesis

  • 0Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Functional & Integrative Genomics +

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July 11, 2025

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July 11, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Silencing USP6NL in colorectal cancer (CRC) cells significantly reduces proliferation and migration while inducing apoptosis. This highlights USP6NL as a potential therapeutic target for CRC, offering a new strategy to combat treatment resistance.

Area Of Science

  • Oncology
  • Molecular Biology
  • Cancer Research

Background

  • Colorectal cancer (CRC) is a major cause of cancer mortality globally.
  • Dysregulated oncogenic pathways drive CRC progression.
  • USP6NL, an endocytic trafficking regulator, is implicated in tumorigenesis, but its role in CRC requires further elucidation.

Purpose Of The Study

  • To investigate the impact of USP6NL knockdown on CRC cell morphology, proliferation, apoptosis, migration, angiogenesis, and metabolic adaptation.
  • To provide mechanistic insights into USP6NL's oncogenic functions in CRC.
  • To explore USP6NL as a potential therapeutic target for CRC, especially in cases resistant to conventional therapies.

Main Methods

  • HCT116 colorectal cancer cells were transfected with USP6NL-specific siRNA.
  • Assessed cell morphology, proliferation (colony formation), migration (wound healing), and apoptosis (flow cytometry).
  • Analyzed gene expression of 84 cancer-related genes using RT²-Profiler PCR array.

Main Results

  • USP6NL depletion induced significant morphological changes and late apoptosis (20.99% vs. 2.69%).
  • Reduced clonogenic potential and impaired cell migration were observed.
  • Inhibited epithelial-mesenchymal transition (EMT) by suppressing VEGFC, ANGPT2, FOXC2, SNAI1, and SNAI2; activated intrinsic apoptosis; and impaired hypoxic adaptation.

Conclusions

  • USP6NL is a key modulator of CRC progression, influencing proliferation, apoptosis, migration, angiogenesis, and metabolism.
  • USP6NL loss suppresses EMT, induces apoptosis, and reduces tumor cell viability, positioning it as a therapeutic target.
  • Targeting USP6NL may enhance tumor cell death, limit metastasis, and improve efficacy when combined with existing therapies.

Keywords:

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