Early growth response 4 is involved in cell proliferation of small cell lung cancer through transcriptional activation of its downstream genes

• Published in: PloS one 2014-11, Vol.9 (11), p.e113606-e113606
• Main Authors: Matsuo, Taisuke, Dat, Le Tan, Komatsu, Masato, Yoshimaru, Tetsuro, Daizumoto, Kei, Sone, Saburo, Nishioka, Yasuhiko, Katagiri, Toyomasa
• Format: Article
• Language: English
• Subjects: Alternative splicing; Analysis; Animals; Antineoplastic drugs; Antitumor agents; Biocompatibility; Biology and Life Sciences; Biomedical materials; Bone cancer; Bone growth; Cancer; Cell growth; Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; Deoxyribonucleic acid; Depletion; DNA; Drug development; Drugs; Early Growth Response Transcription Factors - antagonists & inhibitors; Early Growth Response Transcription Factors - genetics; Early Growth Response Transcription Factors - metabolism; EGR-4 protein; Gene expression; Gene regulation; Genes; Genetic aspects; Genomes; Growth; HEK293 Cells; Homeodomain Proteins - antagonists & inhibitors; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Infertility; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukin-8 - genetics; Interleukin-8 - metabolism; Luciferase; Lung cancer; Lung diseases; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medicine; Medicine and Health Sciences; Metastases; Metastasis; Mice; Microfilament Proteins - antagonists & inhibitors; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; NIH 3T3 Cells; Oncology; Osteolysis; Paracrine Communication; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - genetics; Parathyroid Hormone-Related Protein - metabolism; Proteins; rab GTP-Binding Proteins - antagonists & inhibitors; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; RANK Ligand - genetics; RANK Ligand - metabolism; Recruitment; Rodents; Secretion; siRNA; Small cell lung cancer; Small cell lung carcinoma; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Target recognition; Transcription (Genetics); Transcription activation; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Up-Regulation; Zinc; Zinc finger proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113606

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.