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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1424-1433.
Prepublished online as a Blood First Edition Paper on June 9, 2008; DOI 10.1182/blood-2008-01-133769.
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Submitted January 14, 2008
Accepted May 24, 2008
Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines
Daniela Buglio, Georgios V Georgiakis, Shino Hanabuchi, Kazuhiko Arima, Noor M. Khaskhely, Yong-Jun Liu, and Anas Younes*
Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX, United States
Immunology, MD Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: ayounes{at}mdanderson.org.
Epigenetic changes have been implicated in silencing several B-cell genes in Hodgkin and Reed-Sternberg cells (HRS) of Hodgkin lymphoma (HL), and this mechanism has been proposed to promote HRS survival and escape from immunosurveillance. However, the molecular and functional consequences of histone deacetylase (HDAC) inhibition in HL have not been previously described. In this study, we report that the HDAC inhibitor vorinostat induced p21 expression and decreased Bcl-xL levels causing cell cycle arrest and apoptosis. Furthermore, vorinostat inhibited STAT6 phosphorylation and decreased its mRNA levels in a dose- and time-dependent manner, which was associated with a decrease in the expression and secretion of Thymus and Activation-Regulated Chemokine (TARC/CCL17) and interleukin (IL)-5 and an increase in IP-10 levels. Moreover, vorinostat inhibited TARC secretion by dendritic cells that were activated by the thymic stromal lymphopoietin (TSLP). Collectively, these data suggest that pharmacologic HDAC inhibition in HL may induce favorable anti-tumor activity by a direct antiproliferative effect on HRS cells, and possibly by an immune mediated effect by altering cytokine and chemokines secretion in the microenvironment.
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