Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation

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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