Journal article
Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B cell lymphoma: Implications for epigenetic therapy
Leukemia, Vol.28(1), pp.147-154
01/01/2014
DOI: 10.1038/leu.2013.251
PMCID: PMC4036221
PMID: 23979523
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. DZNep, a histone methyltransferase inhibitor, decreased the H3K27me3 mark while 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.
Details
- Title: Subtitle
- Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B cell lymphoma: Implications for epigenetic therapy
- Creators
- Thomas E. Witzig - Mayo ClinicGuangzhen Hu - Mayo ClinicSteven M. Offer - Mayo ClinicLinda E. Wellik - Mayo ClinicJing Jing Han - Mayo ClinicMary J. Stenson - Mayo ClinicAhmet Dogan - Memorial Sloan Kettering Cancer CenterRobert B. Diasio - Mayo ClinicMamta Gupta - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Leukemia, Vol.28(1), pp.147-154
- DOI
- 10.1038/leu.2013.251
- PMID
- 23979523
- PMCID
- PMC4036221
- ISSN
- 0887-6924
- eISSN
- 1476-5551
- Language
- English
- Date published
- 01/01/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984618650002771
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