FBW7 suppresses ovarian cancer development by targeting the N(6)-methyladenosine binding protein YTHDF2.
FBW7 suppresses ovarian cancer development by targeting the N(6)-methyladenosine binding protein YTHDF2.
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FBW7 通过靶向 N-6-甲基腺苷结合蛋白 YTHDF2 抑制卵巢癌的发展
DOI：
10.1186/s12943-021-01340-8
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发表时间：
2021-03-03
期刊：
影响因子：
37.3
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Xu F;Li J;Ni M;Cheng J;Zhao H;Wang S;Zhou X;Wu X
肿瘤抑制因子FBW 7是SCF E3-泛素连接酶复合物的底物识别组分，其介导各种致癌蛋白的蛋白水解降解。然而，FBW 7在卵巢癌进展中的作用仍然没有得到充分的理解。IP-MASS、co-IP、免疫组织化学和蛋白质印迹法用于鉴定FBW 7在卵巢癌中的潜在底物。使用体外和体内模型研究FBW 7的生物学效应。采用LC/MS法检测卵巢癌组织中m6 A的表达。MeRIP-Seq和RNA-Seq用于评估YTHDF 2的下游靶标。我们发现FBW 7在卵巢癌组织中显著下调，其高表达与良好的预后和升高的m6 A修饰水平相关。一致地，异位FBW 7在体外和体内抑制卵巢癌细胞存活和增殖，而FBW 7的消融使卵巢癌细胞增殖。此外，m6 A阅读器蛋白YTHDF 2被鉴定为FBW 7的新型底物。FBW 7通过诱导YTHDF 2在卵巢癌中的蛋白酶体降解来抵消YTHDF 2的促肿瘤作用。此外，YTHDF 2在全局上调节m6 A修饰的mRNA的周转，包括促凋亡基因BMF。我们的研究表明，FBW 7通过拮抗卵巢癌中YTHDF 2介导的BMF mRNA衰减来抑制肿瘤生长和进展。在线版本包含补充材料，可通过10.1186/s12943-021-01340-8获得。
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. 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. 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. Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer. The online version contains supplementary material available at 10.1186/s12943-021-01340-8.
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影响因子：
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