Hypoxia-induced downregulation of DUSP-2 phosphatase drives colon cancer stemness

Pei Chi Hou, Yo Hua Li, Shih Chieh Lin, Shau Chieh Lin, Jenq Chang Lee, Bo Wen Lin, Jing Ping Liou, Jang Yang Chang, Ching Chuan Kuo, Yi Min Liu, H. Sunny Sun, Shaw Jenq Tsai

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4305-4316
Number of pages12
JournalCancer Research
Volume77
Issue number16
DOIs
Publication statusPublished - Aug 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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