title: 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).
  
  
  OBJECTIVE
  About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the 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.
authors: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Xiaolan
authors: X
authors: Yu
authors: Abdel-Malek
authors: AM
authors: Shahir
authors: Jingfeng
authors: J
authors: Sha
authors: Zhimin
authors: Z
authors: Feng
authors: Betty
authors: B
authors: Eapen
authors: Stanley
authors: S
authors: Nithianantham
authors: Biswajit
authors: B
authors: Das
authors: Jonathan
authors: J
authors: Karn
authors: Aaron
authors: A
authors: Weinberg
authors: Nabil F
authors: NF
authors: Bissada
authors: Fengchun
authors: F
authors: Ye
mesh_terms: D000328:Adult; D000368:Aged; D060085:Coinfection / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology* / Q000821:virology*; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D005260:Female; D016967:Fusobacterium nucleatum / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010510:Periodontal Diseases / Q000382:microbiology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D014779:Virus Replication
chemical_list: D005232:Fatty Acids, Volatile; D012097:Repressor Proteins; C407843:SUV39H1 protein, human; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2