title: Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation.
abstract: Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson's disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients. Targeted DJ-1 knockdown using siRNAs induced necroptosis in myeloma cells. We found that Krüppel-like factor 6 (KLF6) is expressed at lower levels in myeloma cells compared to PBMCs, and DJ-1 knockdown increased KLF6 expression in myeloma cells. Targeted knockdown of KLF6 expression in DJ-1 knockdown myeloma cells rescued these cells from undergoing cell death. Higher DJ-1 levels were observed in bortezomib-resistant myeloma cells compared to parent cells, and siRNA-mediated DJ-1 knockdown reversed bortezomib resistance. DJ-1 knockdown increased KLF6 expression in bortezomib-resistant myeloma cells, and subsequent siRNA-mediated KLF6 knockdown rescued bortezomib-resistant myeloma cells from undergoing cell death. We also demonstrated that specific siRNA-mediated DJ-1 knockdown reduced myeloma cell growth under a hypoxic microenvironment. DJ-1 knockdown reduced the expression of HIF-1α and its target genes in hypoxic-myeloma cells, and overcame hypoxia-induced bortezomib resistance. Our findings demonstrate that elevated DJ-1 levels correlate with myeloma cell survival and acquisition of bortezomib resistance. Thus, we propose that inhibiting DJ-1 may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM patients.
authors.affiliation: School of Natural Sciences, Griffith University, Nathan Campus, Brisbane, QLD, 4111, Australia.|Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, 4111, Australia.
authors.forename: Prahlad V
authors.initials: PV
authors.lastname: Raninga
authors.affiliation: School of Natural Sciences, Griffith University, Nathan Campus, Brisbane, QLD, 4111, Australia.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Di Trapani
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.|School of Medicine, University of Queensland, Herston, QLD, 4072, Australia.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.affiliation: School of Natural Sciences, Griffith University, Nathan Campus, Brisbane, QLD, 4111, Australia. K.Tonissen@griffith.edu.au.|Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, 4111, Australia. K.Tonissen@griffith.edu.au.
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Tonissen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D000075723:Kruppel-Like Factor 6 / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000071617:Protein Deglycase DJ-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D000075723:Kruppel-Like Factor 6; D000069286:Bortezomib; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1
keywords: DJ-1; Drug resistance; Hypoxia; KLF6; Multiple myeloma; Necroptosis