Fei Xu1,2, Jiajia Li1,2, Mengdong Ni1,2, Jingyi Cheng1,2, Haiyun Zhao1,2, Shanshan Wang2,3, Xiang Zhou4,5, Xiaohua Wu6,7. 1. Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. 3. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. 4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. xiangzhou@fudan.edu.cn. 5. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. xiangzhou@fudan.edu.cn. 6. Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. wu.xh@fudan.edu.cn. 7. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. wu.xh@fudan.edu.cn.
Abstract
BACKGROUND: The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. METHODS: IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. RESULTS: We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF. CONCLUSIONS: Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.
BACKGROUND: The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. METHODS: IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. RESULTS: We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF. CONCLUSIONS: Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.
Authors: Jonathan E Grim; Sue E Knoblaugh; Katherine A Guthrie; Amanda Hagar; Jherek Swanger; Jessica Hespelt; Jeffrey J Delrow; Tom Small; William M Grady; Keiichi I Nakayama; Bruce E Clurman Journal: Mol Cell Biol Date: 2012-04-02 Impact factor: 4.272