Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma: implications for epigenetic therapy

• Published in: Leukemia Vol. 28; no. 1; pp. 147 - 154
• Main Authors: Witzig, T E, Hu, G, Offer, S M, Wellik, L E, Han, J J, Stenson, M J, Dogan, A, Diasio, R B, Gupta, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2014; Nature Publishing Group
• Subjects: 631/208/2489/2487/2486; 631/67/1059; 631/67/1990/291/1621/1915; Base Sequence; Cancer Research; Cells; Chromatin Immunoprecipitation; CpG Islands; Critical Care Medicine; DNA Methylation; DNA Primers; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Genetic aspects; Genetic research; Hematology; Humans; Identification and classification; Intensive; Internal Medicine; Kinases; Leukemia; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphoma, Large B-Cell, Diffuse - therapy; Lymphomas; Medicine; Medicine & Public Health; Oncology; original-article; Patients; Phosphatase; Phosphatases; Phosphoprotein Phosphatases - antagonists & inhibitors; Polymerase Chain Reaction; Promoter Regions, Genetic; Proteins; Signal transduction; Tumors; United States > US; CpG methylation; histone methylation; DLBCL; PTPN6; azacytidine; LBH589
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.251

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.