TY - JOUR
T1 - Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3, GATA6, and TWIST1 in the Sezary Syndrome
AU - Wong, Henry K.
AU - Gibson, Heather
AU - Hake, Timothy
AU - Geyer, Susan
AU - Frederickson, Julie
AU - Marcucci, Guido
AU - Caligiuri, Michael A.
AU - Porcu, Pierluigi
AU - Mishra, Anjali
N1 - Publisher Copyright:
© 2015 The Society for Investigative Dermatology.
PY - 2015/8/21
Y1 - 2015/8/21
N2 - 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.
AB - 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.
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U2 - 10.1038/jid.2015.116
DO - 10.1038/jid.2015.116
M3 - Article
C2 - 25806852
AN - SCOPUS:84937634087
SN - 0022-202X
VL - 135
SP - 2084
EP - 2092
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 8
ER -