title: STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain.
abstract: Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for cancer therapy.
authors.affiliation: Department of Oncology and Radiation Medicine, and Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Timofeeva
authors.forename: Nadya I
authors.initials: NI
authors.lastname: Tarasova
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhang
authors.forename: Sergey
authors.initials: S
authors.lastname: Chasovskikh
authors.forename: Amrita K
authors.initials: AK
authors.lastname: Cheema
authors.forename: Honghe
authors.initials: H
authors.lastname: Wang
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Anatoly
authors.initials: A
authors.lastname: Dritschilo
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human