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. 2022 Jul 25:12:913815.
doi: 10.3389/fcimb.2022.913815. eCollection 2022.

Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration

Jianwei Wang  1   2   3 , Zhi Liu  1   2 , Yuyu Xu  1   2 , Yipeng Wang  1   2 , Fei Wang  1 , Qingqing Zhang  1   2 , Chunhua Ni  4 , Yi Zhen  5 , Rui Xu  1   2 , Qisha Liu  1   2 , Weijia Fang  5 , Ping Huang  4 , Xingyin Liu  1   2   6
Affiliations

Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration

Jianwei Wang et al. Front Cell Infect Microbiol. .

Abstract

Gut microbes participate in pathogenesis by interacting with the host genome through epigenetic mechanisms, such as long non-coding RNAs. However, the mechanisms by which the microbiota induce expression alteration of long non-coding RNAs remains unclear. Here, we quantified the transcriptome alteration of human colon cell lines after being infected by a common enteric pathogen Salmonella typhimurium SL1344. We observed a widespread lncRNAs expression alteration. Among them, the elevated expression of LINC00152 was verified and proved to be induced by enteric bacteria-derived lipopolysaccharide (LPS). The inducible LINC00152 were found to inhibit Salmonella invasion and inflammation response. LINC00152 was overexpressed in tumors of the clinical CRC samples compared with adjacent normal tissues. Accordingly, we also demonstrated that overexpression of LINC00152 promoted the migration and invasion of colorectal cancer cells. Consistently, we observed an increased abundance of gram-negative bacteria and LPS in tumors tissue. Taken together, the above data implicated that enriched gram-negative bacteria in tumor tissue might promote tumor growth through modulating the expression of LINC00152. Furthermore, we demonstrated that LPS upregulated the expression of LINC00152 by introducing histone lactylation on its promoter and decreasing the binding efficiency of the repressor, YY1, to it. Our results provide new insights into how enterobacteria affect host epigenetics in human disease.

Keywords: colorectal cancer; enteric bacteria; histone lactylation; lipopolysaccharide; lncRNA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
LPS induced alteration of lncRNA expression. (A) Heatmap of lncRNA expression in Salmonella infected human intestinal epithelial HCT116 cells (ST) and controls(C). (B) The enriched biological process of differential lncRNAs based on the co-expressed protein-coding genes. (C) The heatmap of the top 20 expressed lncRNA in the control and Salmonella infected HCT116 cells. (D, E) qPCR validation of the elevated expression of LNC_ LINC00152 in the S. typhimurium infected HCT116 cells (D) and HEK293T cells (E). (F, H) The expression of LINC00152 in the heat-treated gram-negative bacteria-infected HCT116. (I, J) The expression of LINC00152 in the LPS treated HCT116 and macrophage. *P < 0.05; ***P < 0.001 ****P < 0.0001. All experiments were in three replicates.
Figure 2
Figure 2
LINC00152 is involved in the S. typhimurium-introduced inflammation and cancer cell invasion and migration. (A) The expression level of LINC00152 in the control and overexpressed stalely cells. (B) LINC00152 overexpressed cells had fewer internalized Salmonella. (C) The number of bacteria attachment with cells in control and LINC00152-overexpressed cells. (D, E) The expression level of IL-8 and TNF α were reduced in the LINC00152 overexpressed cells compared with control HCT116 cells infected with S. typhimurium. (F) The migration and invasion of LINC00152 overexpressed HCT116 cells. All experiments were in three replicates. *P < 0.05; **P < 0.01; ***P < 0.001; n.s: not significant.
Figure 3
Figure 3
lncRNA expression and bacteria abundance of CRC samples. (A-C) The expression of LINC00152 in TCGA colorectal samples (A), our clinical CRC samples (B), and the HCT116 cell (C). (D) The level of LPS in tumor tissue and the adjacent normal mucosa. Experiment was performed in three replicates. (E) The differential species between tumor tissues (N=44) and the adjacent normal ones (N=44). Red and purple labeled species are gram-positive and negative bacteria, respectively. (F) The expression of gram-negative bacteria in tissue and normal samples. (G) The increased LPS-assembly lipoprotein in tumor tissue compared with normal tissue adjacent to the tumor. *P < 0.05; **P < 0.01; ***P < 0.001; n.s: not significant.
Figure 4
Figure 4
The epigenetic modifications of bacteria-introduced lncRNA. (A) LPS induced an elevated level of lactic acid in HCT116 cells. (B) The expression of LINC00152 level in the lactic acid-treated cells (N=3). (C) The level of histone lysine lactylation in the LPS treated cells (N=3). (D) ChIP-qPCR revealed that the binding signaling of H4K8la to the LINC00152 promoter regions was higher than in the LPS treated cells compared with control group (N=3). (E) The expression of YY1 upon LPS and lactic acid treatment (N=2). (F) LPS reduced the binding efficiency of YY1 to the LINC00152 promoter compared with the control group (N=3). *P < 0.05; **P < 0.01 ***P < 0.001.
Figure 5
Figure 5
The graphic summary of this study. The enterobacterial LPS induced widespread expression alteration of lncRNAs, including LINC00152. The bacteria-derived LPS upregulates the expression of LINC00152 by introducing histone lactylation on its promoter, and decreasing the binding efficiency of YY1 to it. The LPS-induced overexpression of LINC00152 was linked to the inflammation response and cancer cells migration and invasion.
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