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SIRT5 loss promotes hepatocarcinogenesis via bile acid-induced immunosuppressive microenvironment

ABSTRACT: SIRT5 loss promotes hepatocarcinogenesis via bile acid-induced immunosuppressive microenvironment

PROVIDER: PRJNA795446 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17483090_1.fastq.gz	Fastqsanger.gz
	SRR17483090_2.fastq.gz	Fastqsanger.gz
	SRR17483091_1.fastq.gz	Fastqsanger.gz
	SRR17483091_2.fastq.gz	Fastqsanger.gz
	SRR17483092_1.fastq.gz	Fastqsanger.gz

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SIRT5 loss promotes hepatocarcinogenesis via bile acid-induced immunosuppressive microenvironment

Project description:Hepatocellular carcinoma (HCC) is a prototypical inflammation-associated cancer and the tumor microenvironment (TME) plays a pivotal role in HCC pathogenesis and response to therapy. The liver is a metabolically active organ, but how liver metabolism impacts TME during HCC development and response to immunotherapy are poorly understood. Here, we show that the metabolic regulator SIRT5 is downregulated in human primary HCC samples, and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, which is due to hypersuccinylation and increased BA biosynthesis in the peroxisome. BA acts as a cell-signaling mediator to stimulate its nuclear receptor and promotes M2-like macrophage polarization, thereby creating an immunosuppressive microenvironment favorable for HCC initiating cells. Furthermore, high serum taurocholic acid, a major primary BA, correlates with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in liver tissue samples from HCC patients. Importantly, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency on promoting M2-like polarized TAMs and liver tumor growth. Our study thus uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC. These results also suggest a potential strategy using clinically proven bile acid sequestrants for the treatment of HCC patients, especially those with decreased SIRT5 and abnormally high BAs.

2022-01-10 | GSE193213 | GEO

Role of SIRT5 in Inhibition of Myocardial Hypertrophy

Project description:SIRT5 is one of the seven members of the NAD+-dependent sirtuin family of protein deacylase that is mainly present in mitochondria and regulates metabolism. In heart, SIRT5 is highly expressed and responsible for succinylation on metabolic enzymes. Although the role of SIRT5 in maintaining cardiac homeostasis under physiological stress and few potential substrates of SIRT5 have been preliminarily revealed, the regulatory network and key cellular signaling pathways involving SIRT5 in myocardial hypertrophy remain largely unknown. Here, we used an established murine model of pressure overload-induced myocardial hypertrophy caused by transverse aortic constriction (TAC) to outline the network and pathway involving SIRT5 in cardiac stress responses. Remarkably, SIRT5 KO mice had enhanced myocardial hypertrophy after TAC surgery compared with wild-type mice.

2024-10-05 | GSE186985 | GEO

RNA-seq of SIRT5-KO cells infected with SARS-CoV-2

Project description:We are studying the role of human sirtuin SIRT5 during viral infection with SARS-CoV-2. We performed RNA-sequencing of WT and SIRT5-KO human lung adenocarinoma A549 cells overexpressing ACE2 (A549-ACE2), in infected and mock-infected conditions. . Our analysis revealed that SARS-CoV-2 replication is attenuated in SIRT5-KO cells. In addition, SIRT5-KO cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication.

2021-11-10 | GSE188382 | GEO

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics.

Project description:Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieve a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye, and is incurable once metastatic. Likewise, SIRT5 is required for efficient tumor formation by melanoma xenografts, and in an autochthonous mouse Braf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably include MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.

2021-05-07 | GSE169205 | GEO

Lysyl Oxidase-Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis.

Project description:Background and aimsLysyl oxidase-like 4 (LOXL4) is an amine oxidase that is primarily involved in extracellular matrix remodeling and is highly expressed in HCC tissues, but its functional role in mediating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of LOXL4 in hepatocarcinogenesis.Approach and resultsHere, we demonstrate that hepatic LOXL4 expression was increased during the liver carcinogenesis in mice concomitantly fed a choline-deficient, l-amino acid-defined diet. LOXL4 was secreted by the neoplastic cells and primarily localized within hepatic macrophages through exosome internalization. Supplementation of LOXL4 had minimal effect on neoplastic cells. In vitro exposure of macrophages to LOXL4 invoked an immunosuppressive phenotype and activated programmed death ligand 1 (PD-L1) expression, which further suppressed the function of CD8+ T cells. Injection of LOXL4 promoted macrophages infiltration into the liver and accelerated tumor growth, which was further abolished by adoptive T-cell transfer or PD-L1 neutralization. Label-free proteomics analysis revealed that the immunosuppressive function of LOXL4 on macrophages primarily relied on interferon (IFN)-mediated signal transducer and activator of transcription-dependent PD-L1 activation. Hydrogen peroxide scavenger or copper chelation on macrophages abolished the IFN-mediated PD-L1 presentation by LOXL4. In human HCC tissue, expression of LOXL4 in CD68+ cells was positively correlated with PD-L1 level. High expression of LOXL4 in CD68+ cells and low expression of CD8A in tumor tissue cooperatively predict poor survival of patients with HCC.ConclusionsLOXL4 facilitates immune evasion by tumor cells and leads to hepatocarcinogenesis. Our study unveils the role of LOXL4 in fostering an immunosuppressive microenvironment during hepatocarcinogenesis.

| S-EPMC8251926 | biostudies-literature

TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment

Project description:TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment

| PRJNA717744 | ENA

Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

Project description:Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

| PRJNA601726 | ENA

TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment II

Project description:TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment II

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TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I

Project description:TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I