title: Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura primarily associated with prior exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Inflammation is thought to be a key element in the pathogenesis of MPM, and recently Kdm6 family members (Kdm6a and Kdm6b) have been identified as playing important roles in inflammatory processes. As such these genes could potentially represent novel candidate targets for intervention in MPM. Using RT-PCR we examined the expression of Kdm6aA and Kdm6b in a panel of MPM cell lines and in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic and sarcomatoid histologies. Both Kdm6a and Kdm6b were found to be significantly overexpressed in MPM at the mRNA level. However, tests examining if targeting therapeutically Kdm6a/b using a specific small molecule inhibitor (GSK-J4) was potentially useful for treating MPM, revealed that anti-proliferative activity was higher at lower drug concentrations in cell lines derived from normal mesothelial cells compared to those derived from malignant cells. Treatments with GSK-J4 were found to be associated with the induction of apoptosis and increased expression of pro-inflammatory cytokines. As such our results demonstrate that whilst members of the Kdm6 family are overexpressed in MPM they may not be suitable candidates for therapy and may elicit a cytokine storm.
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Sian
authors.initials: S
authors.lastname: Cregan
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Maeve
authors.initials: M
authors.lastname: Breslin
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Roche
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Wennstedt
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Lauren
authors.initials: L
authors.lastname: MacDonagh
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Cinaria
authors.initials: C
authors.lastname: Albadri
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.affiliation: HOPE Directorate, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Sinead
authors.initials: S
authors.lastname: Cuffe
authors.affiliation: Department of Histopathology and Morbid Anatomy, Trinity College Dublin, Dublin, Ireland.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Finn
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin 8, Ireland.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Gray
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D000068437:Pemetrexed / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D001552:Benzazepines; D016207:Cytokines; C000593030:GSK-J4; D009687:Nuclear Proteins; D011743:Pyrimidines; D000068437:Pemetrexed; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C523998:KDM6A protein, human; C524220:KDM6B protein, human; D002945:Cisplatin