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Updated: Dec 31, 2025

Assessing Autophagic Flux by Measuring LC3, p62, and LAMP1 Co-localization Using Multispectral Imaging Flow Cytometry
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Assessing Autophagic Flux by Measuring LC3, p62, and LAMP1 Co-localization Using Multispectral Imaging Flow Cytometry

Published on: July 21, 2017

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CHK2-FOXK axis promotes transcriptional control of autophagy programs

Yuping Chen1,2, Jinhuan Wu1,2, Guang Liang3

  • 1Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.

Science Advances
|January 9, 2020
PubMed

Insights

DNA damage triggers autophagy via the CHK2-FOXK pathway, enhancing cellular cleanup. A FOXK mutation causes chemoresistance, but combined treatment with cisplatin and chloroquine can overcome this resistance.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Autophagy is a crucial cellular process for maintaining homeostasis by clearing damaged components.
  • DNA damage response pathways are critical for cellular integrity and survival.
  • Transcriptional regulation plays a key role in modulating cellular processes like autophagy.

Purpose of the Study:

  • To elucidate the role of the CHK2-FOXK axis in DNA damage-induced autophagy.
  • To investigate the mechanism of transcriptional regulation in autophagy.
  • To understand the contribution of FOXK mutations to chemoresistance.

Main Methods:

  • Investigated the interaction between CHK2 and FOXK proteins following DNA damage.
  • Analyzed the effect of FOXK phosphorylation and cytoplasmic trapping on autophagy gene expression.
  • Utilized cancer cell models with wild-type and mutated FOXK to study chemoresistance.
  • Assessed the efficacy of cotreatment with cisplatin and chloroquine in overcoming chemoresistance.

Main Results:

  • Discovered that CHK2 phosphorylates FOXK upon DNA damage, leading to FOXK's cytoplasmic sequestration.
  • Demonstrated that cytoplasmic trapping of FOXK, a transcriptional repressor of autophagy genes (ATGs), induces autophagy.
  • Identified a cancer-derived FOXK mutation that enhances FOXK hyperphosphorylation, leading to increased autophagy and chemoresistance.
  • Showed that cotreatment with cisplatin and chloroquine effectively overcomes FOXK mutation-induced chemoresistance.

Conclusions:

  • The CHK2-FOXK pathway is a key regulator of DNA damage-induced autophagy at the transcriptional level.
  • Dysregulation of this pathway, particularly through FOXK mutations, contributes to cancer chemoresistance.
  • Targeting the CHK2-FOXK-autophagy axis offers potential therapeutic strategies for overcoming chemoresistance.

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