An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas.
The nuclear factor of activated T cells (NFAT) family of transcription factors functions as integrators of multiple signaling pathways by binding to chromatin in combination with other transcription factors and coactivators to regulate genes central for cell growth and survival in hematopoietic cells. Recent experimental evidence has implicated the calcineurin/NFAT signaling pathway in the pathogenesis of various malignancies, including diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanism(s) underlying NFATc1 regulation of genes controlling lymphoma cell growth and survival is still unclear. In this study, we demonstrate that the transcription factor NFATc1 regulates gene expression in DLBCL cells through a chromatin remodeling mechanism that involves recruitment of the SWItch/Sucrose NonFermentable chromatin remodeling complex ATPase enzyme SMARCA4 (also known as Brahma-related gene 1) to NFATc1 targeted gene promoters. The NFATc1/Brahma-related gene 1 complex induces promoter DNase I hypersensitive sites and recruits other transcription factors to the active chromatin site to regulate gene transcription. Targeting NFATc1 with specific small hairpin RNA inhibits DNase I hypersensitive site formation and down-regulates target gene expression. Our data support a novel epigenetic control mechanism for the transcriptional regulation of growth and survival genes by NFATc1 in the pathophysiology of DLBCL and suggests that targeting NFATc1 could potentially have therapeutic value.
Pham
Lan V
LV
Department of Hematopathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA. lvpham@mdanderson.org
Tamayo
Archito T
AT
Li
Changping
C
Bueso-Ramos
Carlos
C
Ford
Richard J
RJ
D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004265:DNA Helicases / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D003850:Deoxyribonuclease I; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D017931:DNA Primers; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D003850:Deoxyribonuclease I; C084108:SMARCA4 protein, human; D004265:DNA Helicases