@article{ddb7b63e6952458f8dba47c1424f76ca,
title = "Hypoxia-induced downregulation of DUSP-2 phosphatase drives colon cancer stemness",
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.",
author = "Hou, {Pei Chi} and Li, {Yo Hua} and Lin, {Shih Chieh} and Lin, {Shau Chieh} and Lee, {Jenq Chang} and Lin, {Bo Wen} and Liou, {Jing Ping} and Chang, {Jang Yang} and Kuo, {Ching Chuan} and Liu, {Yi Min} and Sun, {H. Sunny} and Tsai, {Shaw Jenq}",
note = "Funding Information: We thank Miss Yi-Hsuan Ya, Yi-Chen Tang, and Yen-Yu Lai for valuable technical supports. This work was supported by National Research Program for Biopharmaceuticals (NSC 101-2325-B-006-017), National Health Research Institute (NHRI-EX-102-10244BI), and Top University grant of National Cheng Kung University (D103-35A17). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Funding Information: This work was supported by National Research Program for Biopharmaceu-ticals (NSC 101-2325-B-006-017), National Health Research Institute (NHRI-EX-102-10244BI), and Top University grant of National Cheng Kung University (D103-35A17). Publisher Copyright: {\textcopyright}2017 AACR.",
year = "2017",
month = aug,
day = "15",
doi = "10.1158/0008-5472.CAN-16-2990",
language = "English",
volume = "77",
pages = "4305--4316",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "16",
}
