Energy restriction-mimetic agents induce apoptosis in prostate cancer cells in part through epigenetic activation of KLF6 tumor suppressor gene expression
Journal
Journal of Biological Chemistry
Journal Volume
286
Journal Issue
12
Pages
9968-9976
Date Issued
2011
Author(s)
CHE-MING TENG
Abstract
Although energy restriction has been recognized as an important target for cancer prevention, the mechanism by which energy restriction-mimetic agents (ERMAs) mediate apoptosis remains unclear. By using a novel thiazolidinedione- derived ERMA, CG-12 (Wei, S., Kulp, S. K., and Chen, C. S. (2010) J. Biol. Chem. 285, 9780-9791), vis-?-vis 2-deoxyglucose and glucose deprivation, we obtain evidence that epigenetic activation of the tumor suppressor gene Kruppel-like factor 6 (KLF6) plays a role in ERMA-induced apoptosis in LNCaP prostate cancer cells. KLF6 regulates the expression of many proapoptotic genes, and shRNA-mediated KLF6 knockdown abrogated the ability of ERMAs to induce apoptosis. Chromatin immunoprecipitation analysis indicates that this KLF6 transcriptional activation was associated with increased histone H3 acetylation and histoneH3 lysine 4 trimethylation occupancy at the promoter region. Several lines of evidence demonstrate that the enhancing effect of ERMAs on these active histone marks was mediated through transcriptional repression of histone deacetylases and H3 lysine 4 demethylases by down-regulating Sp1 expression. First, putative Sp1-binding elements are present in the promoters of the affected histone-modifying enzymes, and luciferase reporter assays indicate that site-directed mutagenesis of these Sp1 binding sites significantly diminished the promoter activities. Second, shRNA-mediated knockdown of Sp1 mimicked the repressive effect of energy restriction on these histone-modifying enzymes. Third, ectopic Sp1 expression protected cells from the repressive effect of CG-12 on these histone-modifying enzymes, thereby abolishing the activation of KLF6 expression. Together, these findings underscore the intricate relationship between energy restriction and epigenetic regulation of tumor suppressor gene expression, which has therapeutic relevance to foster novel strategies for prostate cancer therapy. ? 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
SDGs
Other Subjects
Apoptosis; Binding elements; Cancer prevention; Chromatin immunoprecipitation analysis; Enhancing effect; Epigenetic regulation; Glucose deprivation; Histone deacetylases; Histone H3; Induced apoptosis; Kruppel-like factor 6; Luciferase reporter assays; Novel strategies; Pro-apoptotic genes; Promoter activities; Promoter region; Prostate cancer cells; Prostate cancers; Site directed mutagenesis; Sp1 binding sites; Thiazolidinediones; Transcriptional activations; Transcriptional repression; Trimethylation; Tumor suppressor genes; Acetylation; Activation analysis; Amino acids; Binding energy; Binding sites; Biochemistry; Catalysts; Cell death; Diseases; Enzymes; Gene expression; Gene therapy; Glucose; Tumors; Gene expression regulation; 2,4 thiazolidinedione derivative; cg 12; energy restriction mimetic agent; histone deacetylase; histone H3; histone h3 lysine 4; histone H3 lysine 4 deacetylase; transcription factor Sp1; unclassified drug; apoptosis; article; binding site; cancer cell; cell strain LNCaP; controlled study; down regulation; energy restriction; epigenetics; gene expression regulation; gene repression; histone acetylation; kruppel like factor 6 gene; priority journal; promoter region; starvation; transcription initiation; tumor suppressor gene; Acetylation; Apoptosis; Cell Line, Tumor; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Histone Deacetylases; Histones; Humans; Hypoglycemic Agents; Kruppel-Like Transcription Factors; Male; Methylation; Prostatic Neoplasms; Proto-Oncogene Proteins; Response Elements; Sp1 Transcription Factor; Thiazolidinediones; Tumor Suppressor Proteins
Type
journal article