SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways
SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways
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SETD2 通过整合 EZH2 和 AMPK 信号通路限制前列腺癌转移
DOI：
10.1016/j.ccell.2020.05.022
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发表时间：
2020-09-14
期刊：
影响因子：
50.3
通讯作者：
Qin, Jun
中科院分区：
文献类型：
--
作者：
Yuan, Huairui;Han, Ying;Qin, Jun
SETD 2介导的H3 K36 me 3的水平与EZH 2催化的H3 K27 me 3的水平负相关。然而，目前还不清楚这两种酶活性是否在分子上相互交织。在这里，我们报告了SETD 2通过其底物EZH 2延迟前列腺癌（PCa）转移。我们表明，SETD 2甲基化EZH 2，促进EZH 2降解。SETD 2缺陷诱导Polycomb抑制染色质状态，使细胞获得转移性性状。相反，携带非甲基化EZH 2突变体或与EZH 2结合缺陷的SETD 2突变体的小鼠发展转移性PCa。此外，我们确定二甲双胍刺激的AMPK信号在FOXO 3处会聚以刺激SET D2表达。总之，我们的结果表明，SETD 2-EZH 2轴整合了代谢和表观遗传信号，以限制PCa转移。
The level of SETD2-mediated H3K36me3 is inversely correlated with that of EZH2-catalyzed H3K27me3. Nevertheless, it remains unclear whether these two enzymatic activities are molecularly intertwined. Here, we report that SETD2 delays prostate cancer (PCa) metastasis via its substrate EZH2. We show that SETD2 methylates EZH2 which promotes EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state that enables cells to acquire metastatic traits. Conversely, mice harboring nonmethylated EZH2 mutant or SETD2 mutant defective in binding to EZH2 develop metastatic PCa. Furthermore, we identify that metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression. Together, our results demonstrate that the SETD2-EZH2 axis integrates metabolic and epigenetic signaling to restrict PCa metastasis.