Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3, GATA6, and TWIST1 in the Sezary Syndrome

Henry K Wong; Heather Gibson; Timothy Hake; Susan Geyer; Julie Frederickson; Guido Marcucci; Michael A Caligiuri; Pierluigi Porcu; Anjali Mishra

doi:10.1038/jid.2015.116

Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3, GATA6, and TWIST1 in the Sezary Syndrome

J Invest Dermatol. 2015 Aug;135(8):2084-2092. doi: 10.1038/jid.2015.116. Epub 2015 Mar 25.

Authors

Henry K Wong¹, Heather Gibson², Timothy Hake³, Susan Geyer⁴, Julie Frederickson⁵, Guido Marcucci⁶, Michael A Caligiuri⁶, Pierluigi Porcu⁷, Anjali Mishra⁸

Affiliations

¹ Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA. Electronic address: hkwong@uams.edu.
² Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; These authors contributed equally to this work.
³ Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.
⁴ The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
⁵ Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
⁶ The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
⁷ The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA. Electronic address: Pierluigi.Porcu@osumc.edu.
⁸ Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA. Electronic address: Anjali.Mishra@osumc.edu.

PMID: 25806852
DOI: 10.1038/jid.2015.116

Abstract

The Sézary Syndrome (SS) is an aggressive CD4+ leukemic variant of cutaneous T-cell lymphoma. Epigenetic modification of cancer cell genome is often linked to the expression of important cancer-related genes. Here we addressed the hypothesis that, in SS, DNA hypomethylation is involved in upregulation of PLS3, GATA6, and TWIST1, genes that are undetected in normal lymphocytes. Pyrosequencing analysis of CpG rich regions, and CpG dinucleotides within the 5' regulatory regions, confirmed hypomethylation of all three genes in SS, compared with controls. We then studied how methylation regulates PLS3 transcription in vitro using PLS3-negative (Jurkat) and PLS3-positive (HT-1080) cell lines. Treatment with the hypomethylating agent 5-azacytidine induced PLS3 expression in Jurkat cells and in vitro methylation of the cloned PLS3 promoter suppressed luciferase expression in HT-1080 cells. In conclusion, we show that promoter hypomethylation is associated with PLS3, GATA6, and TWIST1 overexpression in SS CD4+ T cells and that methylation can regulate PLS3 expression in vitro. The mechanisms of DNA hypomethylation in vivo and the functional role of PLS3, TWIST1, and GATA6 in SS are being investigated.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Azacitidine / pharmacology
Case-Control Studies
Cell Line
DNA Methylation / physiology*
Female
Fibroblasts / drug effects
Fibroblasts / metabolism
Fibroblasts / pathology
GATA6 Transcription Factor / genetics
GATA6 Transcription Factor / metabolism*
Gene Expression Regulation, Neoplastic / drug effects
Humans
In Vitro Techniques
Jurkat Cells
Lymphocytes / drug effects
Lymphocytes / metabolism
Lymphocytes / pathology
Male
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Microfilament Proteins / genetics
Microfilament Proteins / metabolism*
Middle Aged
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Promoter Regions, Genetic / genetics
RNA, Messenger / drug effects
RNA, Messenger / metabolism
Sezary Syndrome / metabolism*
Sezary Syndrome / pathology
Sezary Syndrome / physiopathology
Skin Neoplasms / metabolism*
Skin Neoplasms / pathology
Skin Neoplasms / physiopathology
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism*
Up-Regulation / physiology*

Substances

GATA6 Transcription Factor
GATA6 protein, human
Membrane Glycoproteins
Microfilament Proteins
Nuclear Proteins
RNA, Messenger
TWIST1 protein, human
Twist-Related Protein 1
plastin
Azacitidine

Grants and funding

R21 CA164911/CA/NCI NIH HHS/United States