c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer
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Liangjing Wang1,2,3,*, Meng Xue1,2,3,*, Daniel C. Chung2,3
1Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, and Institute of Gastroenterology, Zhejiang University, Hangzhou, China
2Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
3Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
*These authors contributed equally to this work
Daniel C. Chung, email: Chung.firstname.lastname@example.org
Keywords: c-Myc, HIF-2α, 5-FU, colon cancer
Received: April 30, 2016 Accepted: October 17, 2016 Published: October 26, 2016
Colorectal cancers (CRCs) invariably become hypoxic as they enlarge, and this places unique metabolic demands upon the tumor cells. Hypoxic stress can enhance the invasiveness of cancer cells and induce chemoresistance. c-Myc, an oncogene regulated by hypoxia inducible factors (HIFs), plays a critical role in cell proliferation and metabolism. However, the interplay between c-Myc and HIFs and its clinical significance in hypoxic adaptation in CRCs are unknown. We demonstrate that c-Myc mRNA and protein levels in colon cancer cells are induced within 2 h of hypoxic stress (1% O2) but are then significantly downregulated when exposed to prolonged hypoxia. In chronic hypoxia (over 8 h at 1% O2), HIF-2α but not HIF-1α gradually accumulated in colon cancer cells. Knockdown of HIF-2α increased levels of c-Myc and its downstream target cyclinD1 in chronic hypoxia, indicating that HIF-2α may function to downregulate c-Myc. Chronic hypoxia suppressed the expression of cyclinD1, CDK4, and CDK6, inducing G1 phase block and 5-flurouracil (5-FU) chemoresistance. Overexpression of c-Myc reversed the inhibition of cyclinD1, CDK4, and CDK6, which accelerated the G1/S phase transition under hypoxia and enhanced sensitivity to 5-FU. In contrast, knockdown of c-Myc impaired 5-FU chemosensitivity in colon cancer cells. In summary, HIF-2α plays an important role in regulating the expression of c-Myc in chronic hypoxia, and consequently controls the sensitivity of colon cancer cells to 5-FU treatment in this environment.
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