HIF-1α Regulated WTAP Overexpression Promote Warburg Effect of Ovarian Cancer by m6A-Dependent Manner

Abstract

N6-methyladenosine (m6A), the methylation of the N6 nitrogen on adenosine, acts as the most common internal modification of eukaryotic mRNA. The dynamic and reversible m6A RNA modification established and erased by N6-methyltransferases and demethylases regulates gene expression and determines cell fate. In this study, we find for the first time that exposure of ovarian cancer cells to hypoxia significantly increases the expression of WT1 associated protein(WTAP), a critical m6A methylase which proved to be induced by a hypoxia factor (HIF)-1α dependent manner, and expression of WTAP in ovarian cancer cells is significantly correlated with the clinicopathological characteristics and up-regulation of WTAP predicts poor prognosis of ovarian cancer patients. Knockdown/ Overexpress of WTAP in human ovarian cancer cells substantially reduces/enhances their proliferative and invasive capacity both in vitro and in vivo. Moreover, We discover that WTAP interacts with DGCR8, a vital microprocessor protein, regulating the primary microRNA 200 process in an m6A-dependent manner. Further experiments demonstrate that microRNA200 could positively regulate HK2 and promote Warburg effect. These studies reveal that HIF-1α upregulated WTAP expression mediates primary miRNA processing, accelerates the Warburg effect and promotes the occurrence and development of tumor, thus providing a novel perspective on m6A modification in ovarian cancer progression. Funding Information: This study was supported by grants from the Natural Science Foundation of Anhui Province (2008085QH422). Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: All human ovary tissues were obtained with informed consent, and the ethical review committee approved all protocols of the World Health Organization Collaborating Center for Research in Human Production. Animal studies were approved by the Institutional Animal Care and Use Committee of Second Military Medical University, Shanghai, China.