Dataset Information

Streptococcus anginosus promotes hepatocellular carcinoma progression and BET inhibitor resistance by inducing BRD4 lactylation

ABSTRACT:

Hepatocellular carcinoma (HCC) is a highly aggressive form of carcinoma with a poor prognosis. Diagnostic markers and potential therapeutic targets for HCC are urgently needed. Here, we demonstrate that fecal microbiota transplantation (FMT) using stool samples from HCC patients significantly promote the growth of patient-derived xenografts (PDXs). 16s-rRNA sequencing combined with qPCR reveal that Streptococcus anginosus (S. anginosus) is enriched in the stool samples of HCC patients and HCC-FMT mice. S. anginosus monocolonization recapitulates the tumor-promoting effect of HCC-FMT in germ-free (GF) mice. Mechanistically, S. anginosus plays a critical role in regulating the downstream pathways of BRD4 via its metabolites, thereby promoting the activation of oncogenic Myc and E2F signaling pathways, HCC progression and BET inhibitor (BETi) resistance. S. anginosus-derived lactate promotes BRD4 lactylation at the K317 site via AARS1, thereby inhibiting BRD4 ubiquitination and degradation. Notably, blockade of the S. anginosus-BRD4 lactylation axis improves the BETi responsiveness in both syngeneic mouse models and PDXs. Overall, our study highlights the oncogenic role of the S. anginosus-BRD4 signaling in the gut-liver axis and suggests its potential as a non-invasive biomarker and therapeutic target for HCC.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS12398 | MetaboLights | 2025-12-05

REPOSITORIES: MetaboLights

ACCESS DATA

Similar Datasets

Project description:Purpose: To determine whether previously observed behavioral differences in alcoholic human patients after fecal microbiota transplantation (FMT) could be transferred to mice. Methods: Fecal microbiota samples from a previously published phase 1, double-blind, randomized clinical trial of AUD-related cirrhosis patients were used to colonize germ-free mice. Fecal material was transferred to 10-15-week-old GF C57BL/6 male mice by daily gavage for 3 day. The mice were housed in sterile individually filtered cages for 15 days after which stool was collected and then they underwent the alcohol preference experiment using 2-bottle choice drinking (water and 20% ethanol v/v). Microbial DNA was isolated from stool samples by sequencing the V1 and V2 variable regions of the bacterial 16S rRNA gene were sequenced using Multitag fusion primers and sequenced on an Ion Torrent PGM next-generation sequencer. Intestinal mucosa, liver, and prefrontal cortex tissue was collected from mice at time of sacrifice. RNAseq was used to measure gene expression in pre-FMT and post-FMT samples. RNAseq data were aligned to the mouse genome (GRCm39) using STAR (version 2.7.9a) and counts were generated with HTSeq (version 0.13.5). Genes with very low counts across the study (defined as fewer than 10 counts in more than 2 samples) were eliminated before differential expression analysis. Low count genes were determined separately for each tissue type. The DESeq2 package for R was then used to measure differential expression between pre-FMT and post-FMT mice in the intestine, liver, and PFC. Benjamini and Hochberg False Discovery Rate (FDR) was used to correct for multiple testing with FDR ≤ 0.2 considered significant. Results: Mice colonized with post-FMT stool significantly reduced ethanol acceptance, intake and preference versus pre-FMT colonized mice. Microbial taxa that were higher in post-FMT humans were also associated with lower alcohol intake and preference in mice. RNAseq further showed that differential gene expression, post-FMT, occurred in the intestine rather than the liver and prefrontal cortex. Conclusions: FMT leads to significant change in gut microbiome population, which in turn alters gene expression in the intestine. FMT also significantly affects alcohol consumption. The microbiotal-intestinal interface may alter gut-liver-brain axis and reduce alcohol consumption in humans.

			Action	DRS
	A.raw	Raw
	B.raw	Raw
	C.raw	Raw
	D.raw	Raw
	E.raw	Raw

Dataset Information

Streptococcus anginosus promotes hepatocellular carcinoma progression and BET inhibitor resistance by inducing BRD4 lactylation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets