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Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2
Bartolomeus J Meijer1, Wouter L Smit1, Pim J Koelink1
1Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, Amsterdam, The Netherlands.
Scientific Reports
|May 11, 2021
Summary
Endoplasmic reticulum (ER) stress triggers cancer stem cell differentiation by depleting key transcription factors, including CtBP2, impacting colorectal cancer treatment strategies. This research uncovers new targets for sensitizing cancer cells to therapy.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Biology
Background:
- Cancer stem cell differentiation is a therapeutic target for sensitizing colorectal cancer cells to chemotherapy and irradiation.
- Endoplasmic reticulum (ER) stress activates the unfolded protein response, promoting stem cell differentiation in normal and cancerous intestinal cells.
- Previous work identified Protein kinase R-like ER kinase (PERK)-dependent translational arrest leading to c-MYC depletion as a mechanism for ER stress-induced differentiation.
Purpose of the Study:
- To identify novel transcription factors involved in ER stress-mediated stem cell differentiation.
- To investigate the role of transcription factor CtBP2 in ER stress-induced stemness and colorectal cancer.
- To explore the potential of targeting these factors to enhance cancer therapy.
Main Methods:
- ER stress was induced in LS174T cells using thapsigargin or SubAB.
- Nuclear transcription factor activity was assessed using the CatTFRE assay coupled with mass-spectrometry.
- CtBP2's role was examined through overexpression and knockdown in organoids and cell lines, followed by challenges with ER stress and irradiation.
Main Results:
- A unique set of transcription factors with altered DNA-binding activity upon ER stress was identified.
- Diminished binding of transcription factors involved in cellular differentiation processes was observed.
- ER stress decreased CtBP2 protein expression, a process dependent on PERK signaling, and CtBP2 was overexpressed in colorectal adenomas.
- CtBP2 overexpression enhanced clonogenic potential and radio-resistance in organoids, partially rescuing ER stress-induced stemness loss.
Conclusions:
- CtBP2 mediates ER stress-induced loss of stemness, supporting the stem cell state in both homeostatic and colorectal cancer cells.
- These findings identify novel transcription factors regulated by ER stress and highlight CtBP2 as a key player in maintaining stemness.
- Targeting CtBP2 or related pathways may offer new strategies for colorectal cancer treatment by sensitizing cancer stem cells.
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