A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53.
A G3BP1-Interacting lncRNA Promotes Ferroptosis and Apoptosis in Cancer via Nuclear Sequestration of p53.
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G3BP1 相互作用的 lncRNA 通过 p53 的核隔离促进癌症中的铁死亡和细胞凋亡
DOI：
10.1158/0008-5472.can-17-3454
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发表时间：
2018-07-01
期刊：
影响因子：
11.2
通讯作者：
Tao Y
中科院分区：
文献类型：
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作者：
Mao C;Wang X;Liu Y;Wang M;Yan B;Jiang Y;Shi Y;Shen Y;Liu X;Lai W;Yang R;Xiao D;Cheng Y;Liu S;Zhou H;Cao Y;Yu W;Muegge K;Yu H;Tao Y
长链非编码RNA（lncRNA）与多种类型的癌症有关;然而，许多lncRNA在肿瘤发生中的确切作用仍然难以捉摸。在这里，我们证明了细胞溶质lncRNA P53 RRA在癌症中下调，并通过抑制癌症进展作为肿瘤抑制因子发挥作用。染色质重塑蛋白LSH和Cfp 1分别沉默或增加P53 RRA表达。P53 RRA使用P53 RRA的核苷酸1和871以及G3 BP 1的RRM相互作用结构域（aa 177-466）结合Ras GTP酶激活蛋白结合蛋白1（G3 BP 1）。胞质P53 RRA-G3 BP 1相互作用将p53从G3 BP 1复合物中置换出来，导致更多的p53保留在细胞核中，从而导致细胞周期停滞、凋亡和铁凋亡。P53 RRA通过影响多种代谢基因的转录而促进铁凋亡和细胞凋亡。在携带野生型p53的乳腺癌和肺癌患者中，P53 RRA低表达与生存率低显著相关。这些数据表明，lncRNA可以直接与细胞质中信号蛋白的功能结构域相互作用，从而调节p53调节剂以抑制癌症进展。
Long noncoding RNAs (lncRNA) have been associated with various types of cancer; however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression, respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177–466). The cytosolic P53RRA–G3BP1 interaction displaced p53 from a G3BP1 complex, resulting in greater p53 retention in the nucleus, which led to cell-cycle arrest, apoptosis, and ferroptosis. P53RRA promoted ferroptosis and apoptosis by affecting transcription of several metabolic genes. Low P53RRA expression significantly correlated with poor survival in patients with breast and lung cancers harboring wild-type p53. These data show that lncRNAs can directly interact with the functional domain of signaling proteins in the cytoplasm, thus regulating p53 modulators to suppress cancer progression.