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Title: Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer

Abstract

Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities tomore » understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer.« less

Authors:
; ; ; ;
Publication Date:
OSTI Identifier:
22462155
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 463; Journal Issue: 4; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADHESION; APOPTOSIS; CELL CYCLE; DEATH; GENES; HEAT; HEAT-SHOCK PROTEINS; LUNGS; MOLECULES; NEOPLASMS; PROMOTERS; RECEPTORS; SCREENING; THERAPY; TRANSCRIPTION FACTORS

Citation Formats

Jang, Sang-Min, An, Joo-Hee, Kim, Chul-Hong, Kim, Jung-Woong, E-mail: jungkim@cau.ac.kr, and Choi, Kyung-Hee, E-mail: khchoi@cau.ac.kr. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.06.042.
Jang, Sang-Min, An, Joo-Hee, Kim, Chul-Hong, Kim, Jung-Woong, E-mail: jungkim@cau.ac.kr, & Choi, Kyung-Hee, E-mail: khchoi@cau.ac.kr. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. United States. doi:10.1016/J.BBRC.2015.06.042.
Jang, Sang-Min, An, Joo-Hee, Kim, Chul-Hong, Kim, Jung-Woong, E-mail: jungkim@cau.ac.kr, and Choi, Kyung-Hee, E-mail: khchoi@cau.ac.kr. Fri . "Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer". United States. doi:10.1016/J.BBRC.2015.06.042.
@article{osti_22462155,
title = {Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer},
author = {Jang, Sang-Min and An, Joo-Hee and Kim, Chul-Hong and Kim, Jung-Woong, E-mail: jungkim@cau.ac.kr and Choi, Kyung-Hee, E-mail: khchoi@cau.ac.kr},
abstractNote = {Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer.},
doi = {10.1016/J.BBRC.2015.06.042},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 463,
place = {United States},
year = {Fri Aug 07 00:00:00 EDT 2015},
month = {Fri Aug 07 00:00:00 EDT 2015}
}
  • Human RNA polymerase II (RNAPII)-associated factor 1 complex (hPAF1C) plays a crucial role in protein-coding gene transcription. Overexpression of hPAF1C has been implicated in the initiation and progression of various human cancers. However, the molecular pathways involved in tumorigenesis through hPAF1C remain to be elucidated. The current study suggested hPAF1C expression as a prognostic biomarker for early stage non-small cell lung cancer (NSCLC) and patients with low hPAF1C expression levels had significantly better overall survival. Furthermore, the expression of hPAF1C was found to be positively correlated with c-MYC expression in patient tumor samples and in cancer cell lines. Mechanistic studiesmore » indicated that hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription. These results demonstrated the prognostic value of hPAF1C in early-stage NSCLC and the role of hPAF1C in the transcriptional regulation of c-MYC oncogene during NSCLC tumorigenesis. - Highlights: • hPAF1C expression is a prognostic biomarker for early stage non-small cell lung cancer. • The expression of hPAF1C was positively correlated with c-MYC in tumor samples of patients and in several NSCLC cell lines. • hPAF1C could promote lung cancer cell proliferation through regulating c-MYC transcription.« less
  • The molecular mechanisms reported to regulate the expression of myc family genes are multiple and complex and include gene amplification, transcriptional activation, transcriptional attenuation, and mRNA stability. The authors have investigated which of these mechanisms are responsible for the extreme variation in myc gene family mRNA levels observed in human small-cell lung cancer cell lines. In addition to gene amplification, a block to nascent mRNA chain elongation, causing attenuation of transcription, is an important regulatory mechanism controlling the steady-state levels of c-myc and L-myc in mRNA. The loss of transcriptional attenuation is correlated with overexpression of these two genes inmore » cell lines which do not show gene amplification. Expression of c-myc mRNA appears to be dependent on promoter activity and attenuator function. In contrast, regulation of expression of the N-myc gene does not involve transcriptional attenutation; steady-state mRNA levels are correlated with promoter activity as well as gene amplification. They conclude that transcriptional regulation of each member of the myc gene family is accomplished by a different assortment of complex mechanisms, including gene copy number, promoter activation, and transcriptional attenuation. Interference at multiple points in this complex regulatory process appears to be an important mechanism by which small-cell lung cancer and other human tumors evade growth control.« less
  • Purpose: This study determined practice patterns in the staging and treatment of patients with stage I non-small cell lung cancer (NSCLC) among National Comprehensive Cancer Network (NCCN) member institutions. Secondary aims were to determine trends in the use of definitive therapy, predictors of treatment type, and acute adverse events associated with primary modalities of treatment. Methods and Materials: Data from the National Comprehensive Cancer Network Oncology Outcomes Database from 2007 to 2011 for US patients with stage I NSCLC were used. Main outcome measures included patterns of care, predictors of treatment, acute morbidity, and acute mortality. Results: Seventy-nine percent ofmore » patients received surgery, 16% received definitive radiation therapy (RT), and 3% were not treated. Seventy-four percent of the RT patients received stereotactic body RT (SBRT), and the remainder received nonstereotactic RT (NSRT). Among participating NCCN member institutions, the number of surgeries-to-RT course ratios varied between 1.6 and 34.7 (P<.01), and the SBRT-to-NSRT ratio varied between 0 and 13 (P=.01). Significant variations were also observed in staging practices, with brain imaging 0.33 (0.25-0.43) times as likely and mediastinoscopy 31.26 (21.84-44.76) times more likely for surgical patients than for RT patients. Toxicity rates for surgical and for SBRT patients were similar, although the rates were double for NSRT patients. Conclusions: The variations in treatment observed among NCCN institutions reflects the lack of level I evidence directing the use of surgery or SBRT for stage I NSCLC. In this setting, research of patient and physician preferences may help to guide future decision making.« less
  • Purpose: To identify the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) during {gamma}-ionizing radiation ({gamma}-IR) treatment for non-small-cell lung cancer cells. Methods and Materials: Wild-type PTEN or mutant forms of PTEN plasmids were transfected to construct stable transfectants of the NCI-H1299 non-small-cell lung cancer cell line. Combined effects of PTEN expression and IR treatment were tested using immunoblot, clonogenic, and cell-counting assays. Related signaling pathways were studied with immunoblot and kinase assays. Results: At steady state, stable transfectants showed almost the same proliferation rate but had different AKT phosphorylation patterns. When treated with {gamma}-IR, wild-type PTENmore » transfectants showed higher levels of cell death compared with mock vector or mutant transfectants, and showed increased G{sub 2}/M cell-cycle arrest accompanied by p21 induction and CDK1 inactivation. NCI-H1299 cells were treated with phosphosinositide-3 kinase (PI3K)/AKT pathway inhibitor (LY29002), resulting in reduced AKT phosphorylation levels. Treatment of NCI-H1299 cells with LY29002 and {gamma}-IR resulted in increased cell-cycle arrest and p21 induction. Endogenous wild-type PTEN-containing NCI-H460 cells were treated with PTEN-specific siRNA and then irradiated with {gamma}-IR: however reduced PTEN levels did not induce cell-cycle arrest or p21 expression. Conclusions: Taken together, these findings indicate that PTEN may modulate cell death or the cell cycle via AKT inactivation by PTEN and {gamma}-IR treatment. We also propose that a PTEN-PI3K/AKT-p21-CDK1 pathway could regulate cell death and the cell cycle by {gamma}-IR treatment.« less
  • Migration-stimulating factor (MSF), an oncofetal truncated isoform of fibronectin, is a potent stimulator of cell invasion. However, its distribution and motogenic role in non-small cell lung cancer (NSCLC) have never been identified. In this study, real-time PCR and immunohistochemical staining (IHC) were performed to detect MSF mRNA and protein levels in tumor tissues and matched adjacent tumor-free tissues. Furthermore, to examine the effect of MSF on invasiveness, MSF was upregulated in A549 cells. The invasiveness and viability of A549 cells were then determined using a transwell migration assay and the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assays, respectively. The expression level ofmore » MSF in NSCLC tissue was markedly higher than in matched adjacent tumor-free tissue. Additionally, the level of MSF protein expression in stage III and IV NSCLC samples was higher than in stage I and II NSCLC samples. More importantly, we also demonstrated that migration and invasion of A549 cells increased substantially after upregulating MSF, although proliferation remained unchanged. Meanwhile, we found no correlation between increasing motility and invasiveness of MSF-overexpressing cells and expression levels and activities of matrix metalloprotease MMP-2 and MMP-9. Our current study shows that MSF plays a role in migration and invasion of A549 cells and suggests that MSF may be a potential biomarker of NSCLC progression. - Highlights: • MSF expression was upregulated in NSCLC and correlated with TNM stages. • MSF may be a new biomarker for NSCLC progression. • MSF promoted migration and invasion in A549 cells, independent of MMP-2/MMP-9 expression.« less