Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation.
Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation.
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细菌感染通过调节CDC42乙酰化促进结直肠癌的发生。
DOI：
10.1371/journal.ppat.1011189
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发表时间：
2023-02
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的证据突显了细菌在促进肿瘤发生中的作用。潜在的机制可能是多种多样的，人们对此仍知之甚少。在这里，我们报告沙门氏菌感染导致宿主细胞蛋白质的广泛去乙酰化改变。哺乳动物细胞分裂周期42(CDC42)的乙酰化是Rho家族GTP酶家族的成员之一，参与了癌细胞中许多关键的信号通路，在细菌感染后显著降低。Cdc42被SIRT2脱乙酰化，再被p300/CBP乙酰化。非乙酰化的CDC42在赖氨酸153位显示其下游效应物PAK4的结合受损，p38和JNK的磷酸化减弱，从而减少细胞凋亡。K153乙酰化水平的降低也增强了结肠癌细胞的迁移侵袭能力。结直肠癌(CRC)患者K153乙酰化水平低预示预后不良。综上所述，我们的发现提示了一种新的机制，即通过操纵CDC42乙酰化来调节CDC42-PAK轴，从而促进细菌感染诱导的结直肠肿瘤的发生。蛋白质乙酰化在细胞生命的各个方面起着重要的调节作用。在这项研究中，我们发现沙门氏菌感染干扰了90多种蛋白质的乙酰化，包括Rho GTP酶细胞分裂周期42(CDC42)。CDC42参与了癌细胞中许多重要的信号通路。我们发现，在沙门氏菌感染后，CDC42 K153可以被依赖于NAD+的脱乙酰酶SIRT2去乙酰化，导致其下游效应物PAK4的结合受损。CDC42 K153的低乙酰化水平对肿瘤细胞的迁移、侵袭和凋亡起着至关重要的作用。此外，结直肠癌患者肿瘤组织中K153乙酰化程度低于癌旁正常组织，与结直肠癌患者预后不良有关。总之，从这项研究中获得的信息表明，细菌感染可以通过调节CDC42乙酰化来促进结直肠癌的发生。
Increasing evidence highlights the role of bacteria in promoting tumorigenesis. The underlying mechanisms may be diverse and remain poorly understood. Here, we report that Salmonella infection leads to extensive de/acetylation changes in host cell proteins. The acetylation of mammalian cell division cycle 42 (CDC42), a member of the Rho family of GTPases involved in many crucial signaling pathways in cancer cells, is drastically reduced after bacterial infection. CDC42 is deacetylated by SIRT2 and acetylated by p300/CBP. Non-acetylated CDC42 at lysine 153 shows an impaired binding of its downstream effector PAK4 and an attenuated phosphorylation of p38 and JNK, consequently reduces cell apoptosis. The reduction in K153 acetylation also enhances the migration and invasion ability of colon cancer cells. The low level of K153 acetylation in patients with colorectal cancer (CRC) predicts a poor prognosis. Taken together, our findings suggest a new mechanism of bacterial infection-induced promotion of colorectal tumorigenesis by modulation of the CDC42-PAK axis through manipulation of CDC42 acetylation. Protein acetylation plays an important role in regulating various aspects of cell life. In this study, we show that Salmonella infection disturbs acetylation of more than 90 proteins, including Rho GTPase cell division cycle 42 (CDC42). CDC42 is involved in many crucial signaling pathways in cancer cells. We find that CDC42 K153 can be deacetylated by the NAD+-dependent deacetylase SIRT2 after Salmonella infection, which causes an impaired binding of its downstream effector PAK4. Low acetylation level of CDC42 K153 is crucial for tumor cell migration, invasion and apoptosis. Furthermore, lower K153 acetylation in tumor tissues compared to adjacent normal tissues of colorectal cancer (CRC) patients is correlated to the poor prognosis of CRC. Collectively, the information derived from this study suggests that bacterial infection could promote CRC tumorigenesis by modulating CDC42 acetylation.
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