Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor κB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells
Open Access
- 15 July 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 110 (2) , 735-742
- https://doi.org/10.1182/blood-2006-12-060947
Abstract
Chronic lymphocytic leukemia (CLL) is commonly defined as a disease of failed apoptosis of B cells and remains an incurable disease. The mechanism of resistance to apoptosis in CLL is complex and influenced by numerous factors, including nuclear factor κB (NFκB)-mediated expression of antiapoptotic molecules. Recent evidence indicates that glycogen synthase kinase-3β (GSK-3β) positively regulates NFκB-mediated gene transcription and cell survival. Using malignant B cells collected from patients with CLL, we find that both GSK-3β and NFκB accumulate in the nucleus of CLL B cells, and pharmacologic inhibition of GSK-3 results in decreased expression of two NFκB target genes Bcl-2 and XIAP and a subsequent increase in CLL B-cell apoptosis ex vivo. Furthermore, we observed that inhibition of GSK-3 leads to a decrease in NFκB-mediated gene transcription but does not affect the nuclear accumulation of NFκB in CLL B cells. Last, using chromatin immunoprecipitation, we show that GSK-3 inhibition abrogates NFκB binding to its target gene promoters (XIAP, Bcl-2), in part through epigenetic modification of histones. Our results establish that inhibition of GSK-3 abrogates NFκB binding to its target gene promoters through an epigenetic mechanism, enhances apoptosis in CLL B cells ex vivo and identifies GSK-3 as a potential therapeutic target in the treatment of CLL.Keywords
This publication has 38 references indexed in Scilit:
- Aberrant Nuclear Accumulation of Glycogen Synthase Kinase-3β in Human Pancreatic Cancer: Association with Kinase Activity and Tumor DedifferentiationClinical Cancer Research, 2006
- A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemiaOncogene, 2006
- Deregulated GSK3β activity in colorectal cancer: Its association with tumor cell survival and proliferationBiochemical and Biophysical Research Communications, 2005
- Adaphostin-induced apoptosis in CLL B cells is associated with induction of oxidative stress and exhibits synergy with fludarabineBlood, 2005
- Dynamin 2 regulates T cell activation by controlling actin polymerization at the immunological synapseNature Immunology, 2005
- Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growthOncogene, 2004
- A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cellsLeukemia, 2004
- Role of Histone H3 Lysine 27 Methylation in Polycomb-Group SilencingScience, 2002
- Glycogen synthase kinase-3: functions in oncogenesis and developmentBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1992
- Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survivalBritish Journal of Haematology, 1989