Downregulation of N(6)-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N(6)-methyladenosine levels.
Downregulation of N(6)-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N(6)-methyladenosine levels.
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miR-493-3p介导的N-6-甲基腺苷结合YTHDF2蛋白的下调通过提高N-6-甲基腺苷水平来抑制前列腺癌
DOI：
10.18632/oncotarget.23365
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发表时间：
2018-01-09
期刊：
影响因子：
--
通讯作者：
Xie L
中科院分区：
文献类型：
--
作者：
Li J;Meng S;Xu M;Wang S;He L;Xu X;Wang X;Xie L
近期证据表明，m6A修饰调控多种肿瘤的进展。YTHDF2是一种m6A阅读蛋白，已被证实参与肝细胞癌（HCC）的调控。miR - 493 - 3p被定义为肿瘤抑制因子，可抑制多种癌症的进展。然而，YTHDF2在前列腺癌（PCa）中的功能和机制以及miR - 493 - 3p受m6A间接调控的作用仍不明确。在本研究中，通过免疫组织化学（IHC）染色和显色原位杂交（CISH）发现，在前列腺癌组织和细胞系（DU - 145和PC3）中，YTHDF2经常上调，而miR - 493 - 3p下调，两者呈负相关。敲低YTHDF2可显著提高m6A水平，并抑制DU - 145和PC3细胞系的细胞增殖和迁移。双荧光素酶报告基因检测证实YTHDF2是miR - 493 - 3p的直接靶标。此外，强制表达miR - 493 - 3p可持续提高m6A水平，并在敲低YTHDF2的情况下抑制增殖和迁移。相反，过表达YTHDF2和抑制miR - 493 - 3p则会降低m6A水平。此外，挽救实验表明，抑制miR - 493 - 3p可消除si - YTHDF2诱导的增殖和迁移抑制。总之，YTHDF2和miR - 493 - 3p作为两种关键的m6A调节因子，通过间接调节m6A水平参与前列腺癌的进展。鉴于这些有前景的结果，YTHDF2和miR - 493 - 3p可能为前列腺癌的致癌机制提供新的见解，并为其提供新的潜在治疗靶点。
Recent evidence suggests that m6A modifications regulate the progressions of several types of tumors. YTHDF2, an m6A reader, has been implicated in the regulation of hepatocellular carcinoma (HCC). miR-493-3p has been defined as tumor suppressor that inhibits the progressions of several types of cancers. However, the functions and mechanisms of YTHDF2 and the indirect m6A regulated role of miR-493-3p in prostate cancer (PCa) remains to be elusive. In this study, immuno-histochemical (IHC) staining and chromogenic in situ hybridization (CISH) were performed to find YTHDF2 was frequently upregulated but miR-493-3p was downregulated in both PCa tissues and cell lines (DU-145 and PC3) which was negatively correlated with each other. Knock down of YTHDF2 significantly elevated m6A levels, and inhibited the cell proliferation and migration of DU-145 and PC3 cell lines. The dual-luciferase reporter assay confirmed YTHDF2 as the direct target of miR-493-3p. In addition, forced expression of miR-493-3p consistently elevated the m6A levels and inhibited proliferation and migration with the knock down of YTHDF2. In contrast, overexpression of YTHDF2 and inhibition of miR-493-3p conversely reduced m6A levels. Additionally, the rescue experiments revealed that inhibition of miR-493-3p abrogated the suppression of proliferation and migration induced by si-YTHDF2. To conclude, YTHDF2 and miR-493-3p, as two crucial m6A regulators, are involved in the progression of PCa by indirectly modulating m6A levels. In view of these promising results, YTHDF2 and miR-493-3p may provide new insights into the carcinogenesis and new potential therapeutic targets for PCa.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Schwartz S;Agarwala SD;Mumbach MR;Jovanovic M;Mertins P;Shishkin A;Tabach Y;Mikkelsen TS;Satija R;Ruvkun G;Carr SA;Lander ES;Fink GR;Regev A
通讯作者：
Regev A
N6-甲基腺苷驱动的环状 RNA 的广泛翻译。
影响因子：
44.1
作者：
Yang Y;Fan X;Mao M;Song X;Wu P;Zhang Y;Jin Y;Yang Y;Chen LL;Wang Y;Wong CC;Xiao X;Wang Z
通讯作者：
Wang Z
影响因子：
3.7
作者：
Gu Y;Cheng Y;Song Y;Zhang Z;Deng M;Wang C;Zheng G;He Z
通讯作者：
He Z
YTHDF2 通过直接招募 CCR4-NOT 去腺苷酶复合物来破坏含有 m(6)A 的 RNA 的稳定性。
影响因子：
16.6
作者：
Du, Hao;Zhao, Ya;He, Jinqiu;Zhang, Yao;Xi, Hairui;Liu, Mofang;Ma, Jinbiao;Wu, Ligang
通讯作者：
Wu, Ligang