Systematic Proteome and Lysine Succinylome Analysis Reveals Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Carcinoma.
Systematic Proteome and Lysine Succinylome Analysis Reveals Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Carcinoma.
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系统蛋白质组和赖氨酸琥珀酰组分析揭示食管鳞状细胞癌中低琥珀酰化增强细胞迁移
DOI：
10.1074/mcp.ra120.002150
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Zhang K
中科院分区：
文献类型：
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作者：
Guo Z;Pan F;Peng L;Tian S;Jiao J;Liao L;Lu C;Zhai G;Wu Z;Dong H;Xu X;Wu J;Chen P;Bai X;Lin D;Xu L;Li E;Zhang K
食管鳞状细胞癌（ESCC）是一种侵袭性恶性肿瘤，治疗效果较差。然而，导致ESCC发病机制的蛋白质改变和翻译后修饰（PTMs）仍不清楚。在这里，我们使用定量蛋白质组学方法对ESCC和匹配对照细胞的蛋白质组、磷酰体、赖氨酸乙酰体和琥珀酰体进行了综合表征。我们发现了异常的蛋白质和PTM途径，包括癌细胞中赖氨酸琥珀酰化位点的显著下调。聚焦于下琥珀酰化，我们发现这种改变的PTM在与癌症代谢密不可分的代谢途径的酶上富集。重要的是，一旦琥珀酰化水平在体外或体内恢复，ESCC的恶性行为（如细胞迁移）就会受到抑制。这种效应通过突变破坏候选蛋白中的琥珀酰化位点进一步得到证实。同时，我们发现琥珀酰化对组蛋白甲基化具有负调控作用，促进肿瘤迁移。最后，下琥珀酰化在原发性ESCC标本中得到证实。我们的研究结果共同表明，赖氨酸琥珀酰化可能改变ESCC的代谢和迁移，为PTM在癌症生物学中的功能意义提供了新的见解。定量分析shec和SHEE细胞的蛋白质组学、赖氨酸乙酰酶和琥珀酰酶。赖氨酸琥珀酰化在shec细胞中显著下调。一旦琥珀酰化水平恢复，ESCC的恶性行为受到抑制。低琥珀酰化在原发性ESCC标本中得到证实。测定食管鳞状细胞癌（ESCC）和匹配对照细胞的蛋白质组、磷酸化组、赖氨酸乙酰组和琥珀酰组。我们的研究结果在癌细胞中发现了低琥珀酰化，并发现一旦琥珀酰化水平在体外或体内恢复，ESCC的恶性行为就会受到抑制，这在原发性ESCC标本中得到了进一步证实。我们的研究结果表明，赖氨酸琥珀酰化可能改变ESCC的代谢和迁移，为翻译后修饰在癌症生物学中的功能意义提供了新的见解。
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor therapeutic outcomes. However, the alterations in proteins and posttranslational modifications (PTMs) leading to the pathogenesis of ESCC remain unclear. Here, we provide the comprehensive characterization of the proteome, phosphorylome, lysine acetylome, and succinylome for ESCC and matched control cells using quantitative proteomic approach. We identify abnormal protein and PTM pathways, including significantly downregulated lysine succinylation sites in cancer cells. Focusing on hyposuccinylation, we reveal that this altered PTM was enriched on enzymes of metabolic pathways inextricably linked with cancer metabolism. Importantly, ESCC malignant behaviors such as cell migration are inhibited once the level of succinylation was restored in vitro or in vivo. This effect was further verified by mutations to disrupt succinylation sites in candidate proteins. Meanwhile, we found that succinylation has a negative regulatory effect on histone methylation to promote cancer migration. Finally, hyposuccinylation is confirmed in primary ESCC specimens. Our findings together demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing new insights into the functional significance of PTM in cancer biology. Quantitative proteomes, lysine acetylome, and succinylome of SHEEC and SHEE cells. Lysine succinylation is significantly downregulated in SHEEC cells. ESCC malignant behaviors are inhibited once the level of succinylation is restored. Hyposuccinylation is confirmed in primary ESCC specimens. The proteome, phosphorylome, lysine acetylome, and succinylome were quantified for esophageal squamous cell carcinoma (ESCC) and matched control cells. Our results identify hyposuccinylation in cancer cells and reveal that ESCC malignant behaviors are inhibited once the level of succinylation was restored in vitro or in vivo, which is further confirmed in primary ESCC specimens. Our findings demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing a new insight into the functional significance of posttranslational modification in cancer biology.