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Published on: July 22, 2020
Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon Cancer Stemness
Pei-Chi Hou1, Yo-Hua Li1, Shih-Chieh Lin2
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Abstract:
Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens. Cancer Res; 77(16); 4305-16. ©2017 AACR.
Insights
Hypoxia downregulates DUSP2, promoting colorectal cancer stemness via prostaglandin E2. Inhibiting this pathway or using histone deacetylase inhibitors reverses cancer stemness and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cancer stem-like cells (CSCs) are crucial for tumor growth and resistance.
- Mechanisms driving CSC evolution under stress remain unclear.
Purpose of the Study:
- Investigate the role of dual specificity phosphatase 2 (DUSP2) in CSC accumulation.
- Elucidate the signaling pathways involved in hypoxia-induced CSCs.
Main Methods:
- Assessed DUSP2 expression in colorectal cancer under hypoxia.
- Analyzed prostaglandin E2 (PGE2) production and EP2/EP4 signaling.
- Utilized genetic and pharmacological inhibition of PGE2 pathways.
- Performed genome-wide profiling and histone deacetylase (HDAC) inhibitor treatment.
Main Results:
- Hypoxia downregulates DUSP2, increasing COX-2 and PGE2 production.
- PGE2 promotes CSC stemness via EP2/EP4 signaling, driving tumor growth.
- HDAC inhibitors reversed hypoxia-induced DUSP2 downregulation, COX-2 overexpression, and CSC stemness.
Conclusions:
- DUSP2 downregulation is critical for CSC accumulation in colorectal cancer.
- Targeting PGE2 or using HDAC inhibitors offers potential therapeutic strategies against CSCs.
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