Autophagy of the m(6)A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis.
Autophagy of the m(6)A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis.
复制标题
DOI：
10.1038/s41467-021-22469-6
复制
发表时间：
2021-04-12
影响因子：
16.6
通讯作者：
He YY
中科院分区：
文献类型：
--
作者：
Cui YH;Yang S;Wei J;Shea CR;Zhong W;Wang F;Shah P;Kibriya MG;Cui X;Ahsan H;He C;He YY
在这里，我们表明，FTO作为N6-甲基腺苷（m6 A）RNA去甲基化酶被降解的选择性自噬，这是受损的低水平砷暴露，以促进肿瘤发生。我们发现，在砷相关的人类皮肤病变中，FTO上调，而m6 A RNA甲基化下调。在角质形成细胞中，慢性相关低水平砷暴露上调FTO，下调m6 A RNA甲基化，并诱导恶性转化和肿瘤发生。FTO缺失抑制砷诱导的肿瘤发生。此外，在小鼠中，表皮特异性FTO缺失可防止砷和UVB照射诱导的皮肤肿瘤发生。以FTO为基因靶点或以FTO为靶点可抑制砷转化肿瘤细胞的致瘤性。我们鉴定NEDD 4L为FTO的m6 A修饰的基因靶标。最后，砷通过抑制p62介导的选择性自噬来稳定FTO蛋白。FTO上调可以反过来抑制自噬，导致正反馈回路以维持FTO积累。我们的研究揭示了FTO介导的mRNA m6 A甲基化失调作为促进砷致瘤性的表观转录机制。RNA m6 A脱甲基酶FTO在癌症中具有致癌作用。在这里，作者表明，长期低水平的砷暴露抑制FTO的自噬降解，导致FTO稳定和角质形成细胞中m6 A RNA甲基化减少及其随后的恶性转化。
Here we show that FTO as an N6-methyladenosine (m6A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m6A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m6A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m6A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m6A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity. RNA m6A demethylase FTO has oncogenic roles in cancers. Here the authors show that chronic low-level exposure of arsenic inhibits autophagic degradation of FTO, leading to FTO stabilisation and reduced m6A RNA methylation in keratinocytes and its subsequent malignant transformation.
登录
查看更多内容
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
5
作者：
Argos, Maria;Kalra, Tara;Ahsan, Habibul
通讯作者：
Ahsan, Habibul
影响因子：
10.4
作者：
Burns FJ;Uddin AN;Wu F;Nádas A;Rossman TG
通讯作者：
Rossman TG
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Rudnev D;Evangelista C;Kim IF;Soboleva A;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Edgar R
通讯作者：
Edgar R
影响因子：
3.7
作者：
Gao X;Shin YH;Li M;Wang F;Tong Q;Zhang P
通讯作者：
Zhang P