中國科學家揭示SETD2抑制前列腺癌轉(zhuǎn)移的機制
中國科學院上海營養(yǎng)與健康研究所秦駿研究組、重慶軍醫(yī)大學大坪醫(yī)院江軍研究組、南京醫(yī)科大學王曉明研究組等研究人員合作發(fā)現(xiàn)，SETD2通過整合EZH2和AMPK信號通路來限制前列腺癌的轉(zhuǎn)移。該項研究成果于2020年7月2日在線發(fā)表在《癌細胞》雜志上。
研究人員發(fā)現(xiàn)，SETD2通過其底物EZH2延遲前列腺癌（PCa）轉(zhuǎn)移。研究人員表明，SETD2甲基化EZH2，從而促進EZH2降解。SETD2缺失會引起Polycomb抑制的染色質(zhì)狀態(tài)，進而使細胞能夠獲得轉(zhuǎn)移性狀。相反，攜帶無法甲基化的EZH2突變體或者與EZH2結(jié)合缺陷的SETD2突變體的小鼠會產(chǎn)生轉(zhuǎn)移性PCa。此外，研究人員發(fā)現(xiàn)二甲雙胍刺激的AMPK信號會影響FOXO3來刺激SETD2表達。
總之，這些結(jié)果表明，SETD2-EZH2信號軸整合了代謝和表觀遺傳信號，進而限制PCa的轉(zhuǎn)移。
據(jù)悉，SETD2介導的H3K36me3的水平與EZH2催化的H3K27me3的水平成反比。然而，尚不清楚這兩種酶活性是否在分子上有關聯(lián)。
附：英文原文
Title: SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways
Author: Huairui Yuan, Ying Han, Xuege Wang, Ni Li, Qiuli Liu, Yuye Yin, Hanling Wang, Lulu Pan, Li Li, Kun Song, Tong Qiu, Qiang Pan, Qilong Chen, Guoying Zhang, Yi Zang, Minjia Tan, Jian Zhang, Qintong Li, Xiaoming Wang, Jun Jiang, Jun Qin
Issue&Volume: 2020-07-02
Abstract: The level of SETD2-mediated H3K36me3 is inversely correlated with that of EZH2-catalyzedH3K27me3. Nevertheless, it remains unclear whether these two enzymatic activitiesare molecularly intertwined. Here, we report that SETD2 delays prostate cancer (PCa)metastasis via its substrate EZH2. We show that SETD2 methylates EZH2 which promotesEZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state thatenables cells to acquire metastatic traits. Conversely, mice harboring nonmethylatedEZH2 mutant or SETD2 mutant defective in binding to EZH2 develop metastatic PCa. Furthermore,we identify that metformin-stimulated AMPK signaling converges at FOXO3 to stimulateSETD2 expression. Together, our results demonstrate that the SETD2-EZH2 axis integratesmetabolic and epigenetic signaling to restrict PCa metastasis.
DOI: 10.1016/j.ccell.2020.05.022
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