title: Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma: implications for epigenetic therapy.
abstract: Protein tyrosine phosphatases such as PTPN6 can be downregulated in various neoplasms. PTPN6 expression by immunohistochemistry in 40 diffuse large B-cell lymphoma (DLBCL) tumors was lost or suppressed in 53% (21/40). To elucidate the molecular mechanisms of PTPN6 suppression, we performed a comprehensive epigenetic analysis of PTPN6 promoter 2 (P2). None of the DLBCL primary tumors (0/37) had PTPN6 hypermethylation on the CpG1 island using methylation-specific PCR, pyrosequencing, and high-resolution melting assays. However, hypermethylation in 57% (21/37) of cases was found in a novel CpG island (CpG2) in P2. PTPN6 gene suppression was reversed by 5-aza-deoxycytidine (5-Aza), a DNA methyltransferase inhibitor, and the histone deacetylase inhibitor (HDACi) LBH589. LBH589 and 5-Aza in combination inhibited DLBCL survival and PTPN6 hypermethylation at CpG2. The role of histone modifications was investigated with a chromatin-immunoprecipitation assay demonstrating that PTPN6 P2 is associated with silencing histone marks H3K27me3 and H3K9me3 in DLBCL cells but not normal B cells. 3-Deazaneplanocin A, a histone methyltransferase inhibitor, decreased the H3K27me3 mark, whereas HDACi LBH589 increased the H3K9Ac mark within P2 resulting in re-expression of PTPN6. These studies have uncovered novel epigenetic mechanisms of PTPN6 suppression and suggest that PTPN6 may be a potential target of epigenetic therapy in DLBCL.
authors: Division of Hematology, Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: T E
authors: TE
authors: Witzig
authors: Division of Hematology, Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: G
authors: G
authors: Hu
authors: Department of Molecular and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: S M
authors: SM
authors: Offer
authors: Division of Hematology, Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: L E
authors: LE
authors: Wellik
authors: Division of Hematology, Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: J J
authors: JJ
authors: Han
authors: Division of Hematology, Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: M J
authors: MJ
authors: Stenson
authors: Department of Pathology, Memorial Sloan-Kettering Cancer, New York, NY, USA.
authors: A
authors: A
authors: Dogan
authors: Department of Molecular and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: R B
authors: RB
authors: Diasio
authors: Division of Hematology, Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA.
authors: M
authors: M
authors: Gupta
mesh_terms: D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
chemical_list: D017931:DNA Primers; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6
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