title: KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. 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. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, Ireland.
authors.forename: Sian
authors.initials: S
authors.lastname: Cregan
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Lauran
authors.initials: L
authors.lastname: McDonagh
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, 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, Ireland.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Barr
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, Ireland.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
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: HOPE Directorate, St. James's Hospital, Dublin, Ireland.
authors.forename: Sinead
authors.initials: S
authors.lastname: Cuffe
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, Ireland.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Gray
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008175:Lung Neoplasms / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D008654:Mesothelioma / Q000378:metabolism*; D000086002:Mesothelioma, Malignant; D010997:Pleural Neoplasms / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D018925:Chemokines; D016207:Cytokines; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5