Open AccessHsp90 inhibition increases SOCS3 transcript and regulates migration and cell death in chronic lymphocytic leukemia
Author(s) -
Timothy L. Chen,
Nikhil Gupta,
Amy Lehman,
Amy S. Ruppert,
Lianbo Yu,
Christopher C. Oakes,
Rainer Claus,
Christoph Plass,
Kami J. Maddocks,
Leslie A. Andritsos,
Jeffery A. Jones,
David M. Lucas,
Amy J. Johnson,
John C. Byrd,
Erin Hertlein
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.8760
Subject(s) - socs3 , chronic lymphocytic leukemia , cancer research , biology , gene silencing , hsp90 , protein kinase b , leukemia , carcinogenesis , myeloid leukemia , signal transduction , stat3 , immunology , gene , microbiology and biotechnology , heat shock protein , genetics
Epigenetic or transcriptional silencing of important tumor suppressors has been described to contribute to cell survival and tumorigenesis in chronic lymphocytic leukemia (CLL). Using gene expression microarray analysis, we found that thousands of genes are repressed more than 2-fold in CLL compared to normal B cells; however therapeutic approaches to reverse this have been limited in CLL. Following treatment with the Hsp90 inhibitor 17-DMAG, a significant number of these repressed genes were significantly re-expressed. One of the genes significantly repressed in CLL and up-regulated by 17-DMAG was suppressor of cytokine signaling 3, (SOCS3). SOCS3 has been shown to be silenced in solid tumors as well as myeloid leukemia; however little is known about the regulation in CLL. We found that 17-DMAG induces expression of SOCS3 by via the activation of p38 signaling, and subsequently inhibits AKT and STAT3 phosphorylation resulting in downstream effects on cell migration and survival. We therefore suggest that SOCS3 is an important signaling protein in CLL, and Hsp90 inhibitors represent a novel approach to target transcriptional repression in B cell lymphoproliferative disorders which exhibit a substantial degree of gene repression.