Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7-acetylated and cytoplasm-translocated G protein GαS.
Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7-acetylated and cytoplasm-translocated G protein GαS.
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肝癌祖细胞的恶性进展需要赖氨酸乙酰转移酶7-乙酰化和细胞质转位G蛋白GαS
DOI：
10.1002/hep.32487
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发表时间：
2023-04-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
肝癌发生经过HCC祖细胞（HcPC）完全建立HCC，并且驱动HcPC发展的机制在很大程度上仍然未知。使用基于定量质谱的方法筛选来自二乙基亚硝胺诱导的HCC小鼠模型的非聚集肝细胞和含有HcPC的聚集体中的蛋白质组学分析，以阐明HcPC中的失调蛋白。在肝癌祖细胞HcPC中，异源三聚体G刺激蛋白α亚基（GαS）蛋白水平显著增加，这促进了它们对致癌和促炎细胞因子IL-6的反应，并驱使癌前HcPC完全形成HCC。在机制上，GαS位于肝细胞内的膜上，并在HcPCs中在IL-6的作用下被乙酰转移酶赖氨酸乙酰转移酶7（KAT 7）在K28处乙酰化，导致酰基蛋白硫酯酶1介导的GαS脱棕榈酰化及其胞质易位，这通过GαS K28 A模拟脱乙酰化或K28 Q模拟乙酰化突变小鼠和肝Kat 7敲除小鼠来确定。然后，细胞质乙酰化的GαS与信号转导和转录激活因子3（STAT 3）结合，以阻止其与细胞因子信号转导抑制因子3的相互作用，从而以前馈方式促进HcPC中STAT 3磷酸化和对IL-6的反应。临床上，GαS，特别是K28-乙酰化GαS，在人肝癌前异型增生结节中被确定为增加，并且与增强的STAT 3磷酸化正相关，这与小鼠模型中获得的数据一致。HcPC的恶性进展需要增加K28-乙酰化和细胞质易位的GαS，导致对IL-6的反应增强，并将癌前HcPC驱动为完全建立的HCC，这为预防肝癌发生提供了机制见解和潜在靶点。
Hepatocarcinogenesis goes through HCC progenitor cells (HcPCs) to fully established HCC, and the mechanisms driving the development of HcPCs are still largely unknown. Proteomic analysis in nonaggregated hepatocytes and aggregates containing HcPCs from a diethylnitrosamine‐induced HCC mouse model was screened using a quantitative mass spectrometry–based approach to elucidate the dysregulated proteins in HcPCs. The heterotrimeric G stimulating protein α subunit (GαS) protein level was significantly increased in liver cancer progenitor HcPCs, which promotes their response to oncogenic and proinflammatory cytokine IL‐6 and drives premalignant HcPCs to fully established HCC. Mechanistically, GαS was located at the membrane inside of hepatocytes and acetylated at K28 by acetyltransferase lysine acetyltransferase 7 (KAT7) under IL‐6 in HcPCs, causing the acyl protein thioesterase 1–mediated depalmitoylation of GαS and its cytoplasmic translocation, which were determined by GαS K28A mimicking deacetylation or K28Q mimicking acetylation mutant mice and hepatic Kat7 knockout mouse. Then, cytoplasmic acetylated GαS associated with signal transducer and activator of transcription 3 (STAT3) to impede its interaction with suppressor of cytokine signaling 3, thus promoting in a feedforward manner STAT3 phosphorylation and the response to IL‐6 in HcPCs. Clinically, GαS, especially K28‐acetylated GαS, was determined to be increased in human hepatic premalignant dysplastic nodules and positively correlated with the enhanced STAT3 phosphorylation, which were in accordance with the data obtained in mouse models. Malignant progression of HcPCs requires increased K28‐acetylated and cytoplasm‐translocated GαS, causing enhanced response to IL‐6 and driving premalignant HcPCs to fully established HCC, which provides mechanistic insight and a potential target for preventing hepatocarcinogenesis.
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影响因子：
8
作者：
Wilson, C. H.;McIntyre, R. E.;Arends, M. J.;Adams, D. J.
通讯作者：
Adams, D. J.
影响因子：
64.5
作者：
He G;Dhar D;Nakagawa H;Font-Burgada J;Ogata H;Jiang Y;Shalapour S;Seki E;Yost SE;Jepsen K;Frazer KA;Harismendy O;Hatziapostolou M;Iliopoulos D;Suetsugu A;Hoffman RM;Tateishi R;Koike K;Karin M
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Karin M
肝癌的发生需要通过 CD44 增强的生长因子信号传导抑制 p53
影响因子：
50.3
作者：
Dhar D;Antonucci L;Nakagawa H;Kim JY;Glitzner E;Caruso S;Shalapour S;Yang L;Valasek MA;Lee S;Minnich K;Seki E;Tuckermann J;Sibilia M;Zucman-Rossi J;Karin M
通讯作者：
Karin M
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
14.8
作者：
Mertins P;Tang LC;Krug K;Clark DJ;Gritsenko MA;Chen L;Clauser KR;Clauss TR;Shah P;Gillette MA;Petyuk VA;Thomas SN;Mani DR;Mundt F;Moore RJ;Hu Y;Zhao R;Schnaubelt M;Keshishian H;Monroe ME;Zhang Z;Udeshi ND;Mani D;Davies SR;Townsend RR;Chan DW;Smith RD;Zhang H;Liu T;Carr SA
通讯作者：
Carr SA