RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3
Authors: Arabella Wan
Heng Liang
Ziyou Lin
Xi Li
Xiao-Feng Xiong
Bo Wei
Yi Niu
Honglei Chen
Guohui Wan
Yuan Wang
Lei Sun
Xiaobin Wu
Journal: Molecular Cancer (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Apoptosis; BNIP3; Breast cancer; FTO; N6-methyladenosine.
Affiliations: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China., The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China., The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China., School of Pharmaceutical Sciences, the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China., The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China., The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China. ., The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China. ., School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. ., Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. .

Abstract:  Background: N6-methyladenosine (m6A) modification is the most pervasive modification in mRNA, and has been considered as a new layer of epigenetic regulation on mRNA processing, stability and translation. Despite its functional significance in various physiological processes, the role of the m6A modification involved in breast cancer is yet fully understood. Methods: We used the m6A-RNA immunoprecipitation sequencing to identify the potential targets in breast cancer. To determine the underlying mechanism for the axis of FTO-BNIP3, we performed a series of in vitro and in vivo assays in 3 breast cancer cell lines and 36 primary breast tumor tissues and 12 adjunct tissues. Results: We showed that FTO, a key m6A demethylase, was up-regulated in human breast cancer. High level of FTO was significantly associated with lower survival rates in patients with breast cancer. FTO promoted breast cancer cell proliferation, colony formation and metastasis in vitro and in vivo. We identified BNIP3, a pro-apoptosis gene, as a downstream target of FTO-mediated m6A modification. Epigenetically, FTO mediated m6A demethylation in the 3'UTR of BNIP3 mRNA and induced its degradation via an YTHDF2 independent mechanism. BNIP3 acts as a tumor suppressor and is negatively correlated with FTO expression in clinical breast cancer patients. BNIP3 dramatically alleviated FTO-dependent tumor growth retardation and metastasis. Conclusions: Our findings demonstrate the functional significance of the m6A modification in breast cancer, and suggest that FTO may serve as a novel potential therapeutic target for breast cancer. 

Retracted: No

PubPeer comments:
 Supplemental Figure 4 should contain images of 36 breast tumor tissue, however, in fact, there were 35 breast tumor tissue images shown in the figure. The image shown in red box might contain two samples, but unfortunately, represents one sample in the published files. Could the authors please check?  , 
 The red box contains two different tumor samples. There total 36 samples. ,