Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

Abstract

Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known ifthe oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.

Kaposi's Sarcoma-Associated Herpesvirus Utilizes and Manipulates RNA N 6 -Adenosine Methylation To Promote Lytic Replication

“…Previous studies suggested that the switch of KSHV from latency to productive lytic replication is primarily controlled at the viral chromatin level through histone and DNA modifications (58)(59)(60)(61)(62)(63)(64)(65). In this study, we demonstrate that most KSHV-encoded mRNAs undergo posttranscriptional m 6 A modification.…”

High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus

“…SIRT1 is well known for its antiaging, antioxidative-stress, and anti-inflammation properties (22,47,48), and downregulation of SIRT1 has been linked to the development of diabetes (49). Suppression of SIRT1 has been shown to trigger the reactivation of latent KSHV (42,43). SIRT1 is a member of the sirtuin protein family that couples histone lysine deacetylation to NAD hydrolysis (50)(51)(52).…”

“…To investigate other mechanisms that might be involved in high-glucose induction of KSHV lytic replication, we examined the expression of SIRT1, which is a member of the class III HDACs and a key factor involved in the development of diabetes (34)(35)(36)(37)(38)(39)(40). In addition, several previous studies demonstrated the involvement of SIRT1 in the regulation of KSHV lytic gene expression through epigenetic remodeling (41)(42)(43).…”

From microbe to man: the role of microbial short chain fatty acid metabolites in host cell biology

“…In addition to the gut microbiome, constituents of the oral microbiome produce SCFA metabolites that have similar effects on HDAC1/2 (90). In contrast to the gut where commensal symbiotic microbiota produce SCFAs, in the oral cavity, periodontal pathogens produce SCFAs that downregulate silent information regulator-1 (SIRT1) and two histone N-lysine methyltransferases (HLMTs), EZH1 and SUV39H1, enabling Kaposi sarcoma herpesvirus lytic replication in cell lines and in patients with periodontal disease (90).…”

“…In contrast to the gut where commensal symbiotic microbiota produce SCFAs, in the oral cavity, periodontal pathogens produce SCFAs that downregulate silent information regulator-1 (SIRT1) and two histone N-lysine methyltransferases (HLMTs), EZH1 and SUV39H1, enabling Kaposi sarcoma herpesvirus lytic replication in cell lines and in patients with periodontal disease (90). Saliva of patients with periodontal disease has significantly higher concentrations of butyrate, isobutyrate, and propionate compared with healthy individuals (90).…”