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.

SETD2介导的H3K36me3的水平与EZH2催化的H3K27me3的水平成反比。然而，尚不清楚这两种酶活性是否在分子上交织在一起。在这里，我们报道SETD2通过其底物EZH2延迟前列腺癌（PCa）转移。我们表明SETD2甲基化EZH2，促进EZH2降解。SETD2缺乏症会诱导多梳抑制染色质状态，使细胞能够获得转移性状。相反，带有非甲基化EZH2突变体或SETD2突变体的EZH2结合缺陷的小鼠会产生转移性PCa。此外，我们确定二甲双胍刺激的AMPK信号在FOXO3会聚以刺激SETD2表达。在一起，我们的结果表明SETD2-EZH2轴整合了代谢和表观遗传信号，以限制PCa转移。