c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer
Year: 2016
Type: article
Abstract: // Liangjing Wang 1, 2, 3, * , Meng Xue 1, 2, 3, * , Daniel C. Chung 2, 3 1 Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, and Institute of Gastroenterology, Zhejiang University, Hangzhou, China 2 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 3 Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA * These authors contributed equally to this work Correspondence to: Daniel C. Chung, email: [email protected] Keywords: c-Myc, HIF-2α, 5-FU, colon cancer Received: April 30, 2016 Accepted: October 17, 2016 Published: October 26, 2016 ABSTRACT 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% O 2 ) but are then significantly downregulated when exposed to prolonged hypoxia. In chronic hypoxia (over 8 h at 1% O 2 ), 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.
Source: Oncotarget
Authors: Liangjing Wang, Meng Xue, Daniel C. Chung
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: diamond
Funder: National Cancer Institute
OpenAlex ID: W2540804959