Regulation of senescence escape by the cdk4-EZH2-AP2M1 pathway in response to chemotherapy.
Regulation of senescence escape by the cdk4-EZH2-AP2M1 pathway in response to chemotherapy.
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DOI：
10.1038/s41419-017-0209-y
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Coqueret O
中科院分区：
文献类型：
--
作者：
Le Duff M;Gouju J;Jonchère B;Guillon J;Toutain B;Boissard A;Henry C;Guette C;Lelièvre E;Coqueret O
衰老是一种肿瘤抑制机制，在肿瘤损伤或化疗引起的遗传毒性应激反应中诱导永久性增殖停止。我们最近描述了一些细胞可以逃避这种阻滞，要么是因为衰老不完全，要么是表型适应的结果。抗衰老的恶性细胞表现为更多的抗衰老转化细胞，依赖于Akt和Mcl-1激活的生存途径。在这项研究中，我们进一步表征了衰老逃逸，研究了涌现细胞如何再生。在化疗诱导衰老（chemical -induced escence， CIS）的初始阶段，我们发现cyclin D1表达上调，当其主要伴侣cdk4失活时，细胞涌现被阻止。结果表明，该激酶诱导EZH2甲基化酶上调，EZH2甲基化酶是多梳PRC2复合物的一个组成部分。在治疗的早期阶段，甲基化酶被下调，在避免衰老的克隆中被重新激活。通过siRNA或特定抑制剂使EZH2失活，导致细胞出现特异性抑制。我们使用定量蛋白质组学分析来确定参与衰老逃逸的甲基化酶的新靶标。我们发现了参与受体内吞作用的蛋白，并描述了AP2M1蛋白在控制化疗介导的衰老中的新功能。我们的研究结果表明，AP2M1参与了衰老细胞分泌信号的传递，这表明该途径可能调节参与控制CIS逃逸的特定受体。鉴于这些结果，我们因此提出cdk4-EZH2-AP2M1通路在化疗耐药和衰老逃逸过程中发挥重要作用。由于针对这些蛋白的靶向治疗是可行的，我们建议在对一线基因毒性治疗产生耐药性的结直肠癌或乳腺癌的治疗中进行试验。
Senescence is a tumor suppressive mechanism that induces a permanent proliferative arrest in response to an oncogenic insult or to the genotoxic stress induced by chemotherapy. We have recently described that some cells can escape this arrest, either because senescence was incomplete or as a consequence of a phenotypic adaptation. Malignant cells which resisted senescence emerged as more transformed cells that resist anoikis and rely on survival pathways activated by Akt and Mcl-1. In this study, we further characterize senescence escape, investigating how emergent cells could reproliferate. During the initial step of chemotherapy-induced senescence (CIS), we found that cyclin D1 was upregulated and that cell emergence was prevented when its main partner cdk4 was inactivated. Results indicate that this kinase induced the upregulation of the EZH2 methylase, a component of the polycomb PRC2 complex. Downregulated during the early step of treatment, the methylase was reactivated in clones that escaped senescence. The inactivation of EZH2, either by siRNA or by specific inhibitors, led to a specific inhibition of cell emergence. We used quantitative proteomic analysis to identify new targets of the methylase involved in senescence escape. We identified proteins involved in receptor endocytosis and described new functions for the AP2M1 protein in the control of chemotherapy-mediated senescence. Our results indicate that AP2M1 is involved in the transmission of secreted signals produced by senescent cells, suggesting that this pathway might regulate specific receptors involved in the control of CIS escape. In light of these results, we therefore propose that the cdk4–EZH2–AP2M1 pathway plays an important role during chemotherapy resistance and senescence escape. Since targeted therapies are available against these proteins, we propose that they should be tested in the treatment of colorectal or breast cancers that become resistant to first-line genotoxic therapies.
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影响因子：
4.5
作者：
Iannetti A;Ledoux AC;Tudhope SJ;Sellier H;Zhao B;Mowla S;Moore A;Hummerich H;Gewurz BE;Cockell SJ;Jat PS;Willmore E;Perkins ND
通讯作者：
Perkins ND
影响因子：
9
作者：
Deruy E;Nassour J;Martin N;Vercamer C;Malaquin N;Bertout J;Chelli F;Pourtier A;Pluquet O;Abbadie C
通讯作者：
Abbadie C
影响因子：
10.5
作者：
Barradas, Marta;Anderton, Emma;Gil, Jesus
通讯作者：
Gil, Jesus
影响因子：
10.5
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
12.4
作者：
Leontieva, O. V.;Demidenko, Z. N.;Blagosklonny, M. V.
通讯作者：
Blagosklonny, M. V.