Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma

Implications for epigenetic therapy

Thomas Elmer Witzig, G. Hu, S. M. Offer, L. E. Wellik, J. J. Han, M. J. Stenson, A. Dogan, Robert B Diasio, M. Gupta

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)147-154
Number of pages8
JournalLeukemia
Volume28
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Protein Tyrosine Phosphatases
Lymphoma, Large B-Cell, Diffuse
Epigenomics
Histone Code
Histone Deacetylase Inhibitors
B-Lymphocytes
Neoplasms
Deoxycytidine
CpG Islands
Chromatin Immunoprecipitation
Methyltransferases
Therapeutics
Islands
Methylation
Freezing
Cell Survival
Down-Regulation
Immunohistochemistry
Polymerase Chain Reaction
protein phosphatase 6

Keywords

  • azacytidine
  • CpG methylation
  • DLBCL
  • histone methylation
  • LBH589
  • PTPN6

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma : Implications for epigenetic therapy. / Witzig, Thomas Elmer; Hu, G.; Offer, S. M.; Wellik, L. E.; Han, J. J.; Stenson, M. J.; Dogan, A.; Diasio, Robert B; Gupta, M.

In: Leukemia, Vol. 28, No. 1, 2014, p. 147-154.

Research output: Contribution to journalArticle

Witzig, Thomas Elmer ; Hu, G. ; Offer, S. M. ; Wellik, L. E. ; Han, J. J. ; Stenson, M. J. ; Dogan, A. ; Diasio, Robert B ; Gupta, M. / Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma : Implications for epigenetic therapy. In: Leukemia. 2014 ; Vol. 28, No. 1. pp. 147-154.
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