Dongling Zou1, Lei Dong2, Chenying Li3, Zhe Yin4, Shuan Rao5, Qi Zhou6. 1. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, China. cqzl_zdl@163.com. 2. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA. 3. Department of Hematology, School of Medicine, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310003, China. 4. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, China. 5. Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. raoshuan1@smu.edu.cn. 6. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, China. qizhou9128@163.com.
Abstract
BACKGROUND: Since FTO was recognized as the first m6A demethylase, the understanding of its biological function has been widely expanded. However, the role of FTO in cervical cancer tumorigenesis remains unclear. METHODS: In this study, we first analyzed the expression of FTO in two independent human cancer datasets and evaluated the correlation between FTO level and cervical cancer progression. Using small hairpin RNA technology, we explored the function of FTO in cervical cancer cell line Hela and SiHa cells, respectively. We then determined the FTO targets by performing transcriptional profile with FTO deficient and competent Hela cells, and finally validated these targets with ribosome profiling and functional rescue experiments. RESULTS: Our data suggested that FTO was frequently overexpressed in human cervical cancer tissues and highly correlated with cervical cancer progression. FTO serves as an oncogenic regulator for cervical cancer cells' proliferation and migration which is vastly depended on its demethylase activity. Mechanistically, FTO interacts with transcripts of E2F1 and Myc, inhibition of FTO significantly impairs the translation efficiency of E2F1 and Myc, however, either overexpress E2F1 or Myc sufficiently compensates the FTO deficiency which decreases cell proliferation and migration. CONCLUSIONS: Our study indicates that FTO plays important oncogenic role in regulating cervical cancer cells' proliferation and migration via controlling m6A modification of E2F1 and Myc transcripts. FTO represents a potential drug candidate for cervical cancer therapy.
BACKGROUND: Since FTO was recognized as the first m6A demethylase, the understanding of its biological function has been widely expanded. However, the role of FTO in cervical cancer tumorigenesis remains unclear. METHODS: In this study, we first analyzed the expression of FTO in two independent human cancer datasets and evaluated the correlation between FTO level and cervical cancer progression. Using small hairpin RNA technology, we explored the function of FTO in cervical cancer cell line Hela and SiHa cells, respectively. We then determined the FTO targets by performing transcriptional profile with FTO deficient and competent Hela cells, and finally validated these targets with ribosome profiling and functional rescue experiments. RESULTS: Our data suggested that FTO was frequently overexpressed in human cervical cancer tissues and highly correlated with cervical cancer progression. FTO serves as an oncogenic regulator for cervical cancer cells' proliferation and migration which is vastly depended on its demethylase activity. Mechanistically, FTO interacts with transcripts of E2F1 and Myc, inhibition of FTO significantly impairs the translation efficiency of E2F1 and Myc, however, either overexpress E2F1 or Myc sufficiently compensates the FTO deficiency which decreases cell proliferation and migration. CONCLUSIONS: Our study indicates that FTO plays important oncogenic role in regulating cervical cancer cells' proliferation and migration via controlling m6A modification of E2F1 and Myc transcripts. FTO represents a potential drug candidate for cervical cancer therapy.
Authors: Jacques Ferlay; Isabelle Soerjomataram; Rajesh Dikshit; Sultan Eser; Colin Mathers; Marise Rebelo; Donald Maxwell Parkin; David Forman; Freddie Bray Journal: Int J Cancer Date: 2014-10-09 Impact factor: 7.396