Leukemia inhibitory factor receptor homodimerization mediated by acetylation of extracellular lysine promotes prostate cancer progression through the PDPK1/AKT/GCN5 axis.
Leukemia inhibitory factor receptor homodimerization mediated by acetylation of extracellular lysine promotes prostate cancer progression through the PDPK1/AKT/GCN5 axis.
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细胞外赖氨酸乙酰化介导的白血病抑制因子受体同二聚化通过PDPK1/AKT/GCN5轴促进前列腺癌进展
DOI：
10.1002/ctm2.676
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发表时间：
2022-03
影响因子：
10.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Ding Y;Chi H;Shao J;Shi T;Yu H;Wang X;Wang X
前列腺癌（PCa）是一种惰性肿瘤，具有较长的进展期，但缺乏有效的生物标志物和方法来有效和敏感地监测PCa的进展，这促使我们寻找新的诊断和预后预测因子。表征受体激活的翻译后修饰被认为是疾病进展的潜在强有力的指标。采用液相质谱法、基因工程小鼠（GEM）模型、类器官实验、慢病毒包装、感染和稳定细胞系构建等方法研究了白血病抑制因子受体（LIFR）的转录后调控及其在PCa中的新型下游信号活性。在这项研究中，乙酰化K620在LIFR细胞外区域的水平被证明可以预测PCa的进展和预后。在PCa细胞中，LIFR‐K620乙酰化是由GCN5和SIRT2可逆介导的。GEM实验和类器官分析证实，LIFR‐K620乙酰化的缺失抑制了PCa的进展。机制上，K620乙酰化促进LIFR同二聚化，随后促进LIFR‐S1044磷酸化和激活，进而募集PDPK1激活AKT信号，并通过CRL4Cdt2 E3连接酶阻止GCN5降解，从而提高GCN5蛋白水平，维持LIFR‐K620乙酰化的蛋白水平。细胞外K620在LIFR上的乙酰化增强了其同二聚体化，并整合了PDPK1、AKT、GSK3β和GCN5的活性，在PCa中形成了一个新的正反馈回路；因此，这种修饰是一种很有前途的监测前列腺癌进展的生物标志物。我们首先证明了由K620乙酰化介导的LIFR同型二聚体的形成在前列腺上皮中以AKT依赖的方式上调，并且是PTEN缺失肿瘤恶性肿瘤不可缺少的必要条件。基于这项研究，LIFR‐K620的乙酰化可以作为前列腺癌患者预后的生物标志物进行非侵入性检测，也可以作为潜在的治疗靶点。
Prostate cancer (PCa), an inert tumour, has a long progression period, but valid biomarkers and methods for effectively and sensitively monitoring PCa progression are lacking, prompting us to identify new predictors for diagnosis and prognosis. Posttranslational modifications characterizing receptor activation are considered potentially strong indicators of disease progression. The posttranscriptional regulation of leukaemia inhibitory factor receptor (LIFR) and its novel downstream signalling activity in PCa were studied using liquid mass spectrometry, genetically engineered mouse (GEM) models, organoid assays, lentivirus packaging, infection and stable cell line construction. In this study, the level of acetylated K620 on LIFR in its extracellular domain was shown to predict the progression and prognosis of PCa. In PCa cells, LIFR‐K620 acetylation is reversibly mediated by GCN5 and SIRT2. GEM experiments and organoid assays confirmed that the loss of LIFR‐K620 acetylation inhibits PCa progression. Mechanistically, K620 acetylation facilitates LIFR homodimerization and subsequently promotes LIFR‐S1044 phosphorylation and activation, which further recruits PDPK1 to activate AKT signalling and sequentially enhances the GCN5 protein level to sustain the protumour level of LIFR‐K620 acetylation by preventing GCN5 degradation via CRL4Cdt2 E3 ligase. Acetylation of extracellular K620 on LIFR reinforces its homodimerization and integrates the activities of PDPK1, AKT, GSK3β and GCN5 to form a novel positive feedback loop in PCa; this modification is thus a promising biomarker for monitoring PCa progression. We first demonstrated that LIFR homodimer formation mediated by K620 acetylation is upregulated in the prostate epithelium in an AKT‐dependent manner and is indispensably required for the malignancy of PTEN‐null tumors. Based on this study, the acetylation of LIFR‐K620 can be used as a biomarker for prognosis in prostate cancer patients for non‐invasive testing, and also as a potential therapeutic target.
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影响因子：
82.9
作者：
Hayek SS;Koh KH;Grams ME;Wei C;Ko YA;Li J;Samelko B;Lee H;Dande RR;Lee HW;Hahm E;Peev V;Tracy M;Tardi NJ;Gupta V;Altintas MM;Garborcauskas G;Stojanovic N;Winkler CA;Lipkowitz MS;Tin A;Inker LA;Levey AS;Zeier M;Freedman BI;Kopp JB;Skorecki K;Coresh J;Quyyumi AA;Sever S;Reiser J
通讯作者：
Reiser J
影响因子：
64.5
作者：
Gao D;Vela I;Sboner A;Iaquinta PJ;Karthaus WR;Gopalan A;Dowling C;Wanjala JN;Undvall EA;Arora VK;Wongvipat J;Kossai M;Ramazanoglu S;Barboza LP;Di W;Cao Z;Zhang QF;Sirota I;Ran L;MacDonald TY;Beltran H;Mosquera JM;Touijer KA;Scardino PT;Laudone VP;Curtis KR;Rathkopf DE;Morris MJ;Danila DC;Slovin SF;Solomon SB;Eastham JA;Chi P;Carver B;Rubin MA;Scher HI;Clevers H;Sawyers CL;Chen Y
通讯作者：
Chen Y
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
14.8
作者：
Drost J;Karthaus WR;Gao D;Driehuis E;Sawyers CL;Chen Y;Clevers H
通讯作者：
Clevers H
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL