title: Sphingosine kinase 1 is required for mesothelioma cell proliferation: role of histone acetylation.
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics.
  
  
  RESULTS
  In this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti-acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK1-/- null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts.
  
  
  CONCLUSIONS
  The lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Satish
authors.initials: S
authors.lastname: Kalari
authors.forename: Nagabhushan
authors.initials: N
authors.lastname: Moolky
authors.forename: Srikanth
authors.initials: S
authors.lastname: Pendyala
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Berdyshev
authors.forename: Cleo
authors.initials: C
authors.lastname: Rolle
authors.forename: Rajani
authors.initials: R
authors.lastname: Kanteti
authors.forename: Archana
authors.initials: A
authors.lastname: Kanteti
authors.forename: Wenli
authors.initials: W
authors.lastname: Ma
authors.forename: Donghong
authors.initials: D
authors.lastname: He
authors.forename: Aliya N
authors.initials: AN
authors.lastname: Husain
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Prasad
authors.initials: P
authors.lastname: Kanteti
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008654:Mesothelioma / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D000099157:Sphingosine Kinase
chemical_list: D006657:Histones; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase