title: Early growth response 4 is involved in cell proliferation of small cell lung cancer through transcriptional activation of its downstream genes.
abstract: Small cell lung cancer (SCLC) is aggressive, with rapid growth and frequent bone metastasis; however, its detailed molecular mechanism remains poorly understood. Here, we report the critical role of early growth factor 4 (EGR4), a DNA-binding, zinc-finger transcription factor, in cell proliferation of SCLC. EGR4 overexpression in HEK293T cells conferred significant upregulation of specific splice variants of the parathyroid hormone-related protein (PTHrP) gene, resulting in enhancement of the secretion of PTHrP protein, a known mediator of osteolytic bone metastasis. More importantly, depletion of EGR4 expression by siRNA significantly suppressed growth of the SCLC cell lines, SBC-5, SBC-3 and NCI-H1048. On the other hand, introduction of EGR4 into NIH3T3 cells significantly enhanced cell growth. We identified four EGR4 target genes, SAMD5, RAB15, SYNPO and DLX5, which were the most significantly downregulated genes upon depletion of EGR4 expression in all of the SCLC cells examined, and demonstrated the direct recruitment of EGR4 to their promoters by ChIP and luciferase reporter analysis. Notably, knockdown of the expression of these genes by siRNA remarkably suppressed the growth of all the SCLC cells. Taken together, our findings suggest that EGR4 likely regulates the bone metastasis and proliferation of SCLC cells via transcriptional regulation of several target genes, and may therefore be a promising target for the development of anticancer drugs for SCLC patients.
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Matsuo
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan; Department of Medical Oncology, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Le Tan
authors.initials: le T
authors.lastname: Dat
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Daizumoto
authors.affiliation: Department of Medical Oncology, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.affiliation: Department of Medical Oncology, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D051765:Early Growth Response Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D019899:Paracrine Communication; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051765:Early Growth Response Transcription Factors; D018398:Homeodomain Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D008840:Microfilament Proteins; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D014157:Transcription Factors; D020691:rab GTP-Binding Proteins; C100596:DLX5 protein, human; C111028:EGR4 protein, human; C503967:SYNPO protein, human; C505688:TNFSF11 protein, human; C509341:RAB15 protein, human