FOSL1

Gene Summary

Gene:FOSL1; FOS like 1, AP-1 transcription factor subunit
Aliases: FRA, FRA1, fra-1
Location:11q13.1
Summary:The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:fos-related antigen 1
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Phosphorylation
  • Base Sequence
  • Lung Cancer
  • RTPCR
  • Promoter Regions
  • Cancer RNA
  • Proto-Oncogene Proteins c-jun
  • Epithelial Cells
  • Neoplasm Metastasis
  • Repressor Proteins
  • Gene Knockdown Techniques
  • Antineoplastic Agents
  • Down-Regulation
  • Neoplasm Invasiveness
  • p38 Mitogen-Activated Protein Kinases
  • Breast Cancer
  • Cell Proliferation
  • MicroRNAs
  • Protein Binding
  • Squamous Cell Carcinoma
  • Transcription Factors
  • Chromosome 11
  • Epithelial-Mesenchymal Transition
  • siRNA
  • Messenger RNA
  • Biomarkers, Tumor
  • Oligonucleotide Array Sequence Analysis
  • Colonic Neoplasms
  • Signal Transduction
  • Phenotype
  • Gene Expression Profiling
  • Proto-Oncogene Proteins c-fos
  • Cell Movement
  • Gene Expression
  • MAP Kinase Signaling System
  • Colorectal Cancer
  • Neoplastic Cell Transformation
  • Cancer Gene Expression Regulation
  • Western Blotting
  • Immunohistochemistry
  • DNA-Binding Proteins
Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FOSL1 (cancer-related)

Lau EY, Lo J, Cheng BY, et al.
Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling.
Cell Rep. 2016; 15(6):1175-89 [PubMed] Related Publications
Like normal stem cells, tumor-initiating cells (T-ICs) are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs) would regulate liver T-ICs. We found that the presence of α-SMA(+) CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC.

Cheng F, Su L, Yao C, et al.
SIRT1 promotes epithelial-mesenchymal transition and metastasis in colorectal cancer by regulating Fra-1 expression.
Cancer Lett. 2016; 375(2):274-83 [PubMed] Related Publications
Understanding molecular mechanisms of colorectal cancer (CRC) metastasis is urgently required for targeted therapy and prognosis of metastatic CRC. In this study, we explored potential effects of silent mating type information regulation 2 homolog 1 (SIRT1) on CRC metastasis. Our data showed that ectopic expression of SIRT1 markedly increased the migration and invasion of CRC cells. In contrast, silencing SIRT1 repressed this behavior in aggressive CRC cells. Tumor xenograft experiments revealed that knockdown of SIRT1 impaired CRC metastasis in vivo. Silencing SIRT1 in CRC cells induced mesenchymal-epithelial transition (MET), which is the reverse process of epithelial-mesenchymal transition (EMT) and characterized by a gain of epithelial and loss of mesenchymal markers. We provided a mechanistic insight toward regulation of Fra-1 by SIRT1 and demonstrated a direct link between the SIRT1-Fra-1 axis and EMT. Moreover, SIRT1 expression correlated positively with Fra-1 expression, metastasis and overall survival in patients with CRC. Taken together, our data provide a novel mechanistic role of SIRT1 in CRC metastasis, suggesting that SIRT1 may serve as a potential therapeutic target for metastatic CRC.

Liu X, Li H, Rajurkar M, et al.
Tead and AP1 Coordinate Transcription and Motility.
Cell Rep. 2016; 14(5):1169-80 [PubMed] Free Access to Full Article Related Publications
The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells.

He W, Wu Y, Tang X, et al.
HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.
Oncotarget. 2016; 7(6):6727-47 [PubMed] Free Access to Full Article Related Publications
Activator protein 1 (AP-1) is a transcriptional factor composed of the dimeric members of bZIP proteins, which are frequently deregulated in human cancer cells. In this study, we aimed to identify an oncogenic AP-1 dimer critical for the proliferation of neuroblastoma cells and to investigate whether histone deacetylase inhibitors (HDACIs), a new generation of anticancer agents, could target the AP-1 dimer. We report here that HDACIs including trichostatin A, suberoylanilidehydroxamic acid, valproic acid and M344 can transcriptionally suppress both c-Jun and Fra-1, preceding their inhibition of cell growth. c-Jun preferentially interacting with Fra-1 as a heterodimer is responsible for AP-1 activity and critical for cell growth. Mechanistically, HDACIs suppress Fra-1 expression through transcriptionally downregulating Raf1 and subsequently decreasing MEK1/2-ERK1/2 activity. Unexpectedly, HDACI treatment caused MKK7 downregulation at both the protein and mRNA levels. Deletion analysis of the 5'-flanking sequence of the MKK7 gene revealed that a major element responsible for the downregulation by HDACI is located at -149 to -3 relative to the transcriptional start site. Knockdown of MKK7 but not MKK4 remarkably decreased JNK/c-Jun activity and proliferation, whereas ectopic MKK7-JNK1 reversed HDACI-induced c-Jun suppression. Furthermore, suppression of both MKK-7/c-Jun and Raf-1/Fra-1 activities was involved in the tumor growth inhibitory effects induced by SAHA in SH-SY5Y xenograft mice. Collectively, these findings demonstrated that c-Jun/Fra-1 dimer is critical for neuroblastoma cell growth and that HDACIs act as effective suppressors of the two oncogenes through transcriptionally downregulating MKK7 and Raf1.

Iskit S, Schlicker A, Wessels L, Peeper DS
Fra-1 is a key driver of colon cancer metastasis and a Fra-1 classifier predicts disease-free survival.
Oncotarget. 2015; 6(41):43146-61 [PubMed] Free Access to Full Article Related Publications
Fra-1 (Fos-related antigen-1) is a member of the AP-1 (activator protein-1) family of transcription factors. We previously showed that Fra-1 is necessary for breast cancer cells to metastasize in vivo, and that a classifier comprising genes that are expressed in a Fra-1-dependent fashion can predict breast cancer outcome. Here, we show that Fra-1 plays an important role also in colon cancer progression. Whereas Fra-1 depletion does not affect 2D proliferation of human colon cancer cells, it impairs growth in soft agar and in suspension. Consistently, subcutaneous tumors formed by Fra-1-depleted colon cancer cells are three times smaller than those produced by control cells. Most remarkably, when injected intravenously, Fra-1 depletion causes a 200-fold reduction in tumor burden. Moreover, a Fra-1 classifier generated by comparing RNA profiles of parental and Fra-1-depleted colon cancer cells can predict the prognosis of colon cancer patients. Functional pathway analysis revealed Wnt as one of the central pathways in the classifier, suggesting a possible mechanism of Fra-1 function in colon cancer metastasis. Our results demonstrate that Fra-1 is an important determinant of the metastatic potential of human colon cancer cells, and that the Fra-1 classifier can be used as a prognostic predictor in colon cancer patients.

Zhong G, Chen X, Fang X, et al.
Fra-1 is upregulated in lung cancer tissues and inhibits the apoptosis of lung cancer cells by the P53 signaling pathway.
Oncol Rep. 2016; 35(1):447-53 [PubMed] Related Publications
Fos-related antigen-1 (Fra-1) is a member of the activator protein-1 transcription factor superfamily. It plays important roles in oncogenesis in various types of malignancies. Herein, we investigated the expression of Fra-1 in lung cancer tissues by qPCR, immunohistochemistry, and western blot technologies. The results showed that Fra-1 was overexpressed in the lung cancer tissues when compared with the level in the adjacent non-cancerous tissues. To explore the possible mechanism of Fra-1 in lung cancer, we elucidated the effect of Fra-1 on the apoptosis of lung cancer H460 cells, and found that the rate of cell apoptosis was decreased in the H460/Fra-1 cells compared with the H460 or H460/vector cells. Cell apoptosis is closely related with a reduction in mitochondrial membrane potential (ΔΨm) and an increase in intracellular reactive oxygen species (ROS) and calcium ion (Ca2+) concentrations. Our results showed that overexpression of Fra-1 in the lung cancer H460 cells, led to an increase in ΔΨm and and a decrease in intracellular ROS and Ca2+ concentrations. Furthermore, we found that Fra-1 was correlated with dysregulation of the P53 signaling pathway in lung cancer tissues in vitro. At the same time, we found that Fra-1 overexpression affected the expression of MDM2 and P53 in vivo. In summary, our results suggest that Fra-1 is upregulated in lung cancer tissues and functions by affecting the P53 signaling pathway in lung cancer.

Wu J, Ji A, Wang X, et al.
MicroRNA-195-5p, a new regulator of Fra-1, suppresses the migration and invasion of prostate cancer cells.
J Transl Med. 2015; 13:289 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: An increasing number of studies have demonstrated that deregulation of microRNAs (miRNAs) was a common event in tumor tissues and miRNAs would be treated as ideal tumor biomarkers or therapeutic targets. miR-195-5p (termed as miR-195 for briefly in the following part) was suggested to function as a tumor suppressor in cancer development and progression. However, the roles of miR-195 in human prostate cancer are still elusive. Thus, this study was performed to investigate the biological functions and its molecular mechanisms of miR-195 in human prostate cancer cell lines, discussing whether it has a potential to be a therapeutic way of prostate cancer.
METHODS: Two human prostate cancer cell lines were analyzed for the expression of miR-195 by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). A gain-of-function study of miR-195 was conducted by transfecting mimics into DU145 and PC3 cells and cell motility and invasion ability were evaluated by wound healing assay and transwell assay. Tissue microarray, and immunohistochemistry with antibodies against Fra-1 was performed using the peroxidase and DAB methods. The target gene of miR-195 was determined by luciferase assay, quantitative RT-PCR and western blot. The regulation of motility by miR-195 was analyzed by western blot.
RESULTS: miR-195 was frequently down-regulated in both prostate cancer cell lines, DU145 and PC3. Overexpression of miR-195 significantly repressed the capability of migration and invasion of prostate cancer cells. In addition, we identified Fra-1, a cell motility regulator, as a novel target of miR-195. Fra-1 was up-regulated in prostate cancer tissues. We also observed that inhibition of miR-195 or restoration of Fra-1 in miR-195-over-expressed prostate cancer cells partially reversed the suppressive effects of miR-195. Furthermore, we demonstrated miR-195 could inhibit prostate cancer cell motility by regulated the expression of c-Met, MMP1, MMP9.
CONCLUSIONS: miR-195 can repress the migration and invasion of prostate cancer cells via regulating Fra-1. Our results indicate that miR-195 could be a tumor suppressor and may have a potential to be a diagnostics or therapeutic target in prostate cancer.

He J, Zhu G, Gao L, et al.
Fra-1 is upregulated in gastric cancer tissues and affects the PI3K/Akt and p53 signaling pathway in gastric cancer.
Int J Oncol. 2015; 47(5):1725-34 [PubMed] Related Publications
Gastric cancer is an aggressive disease that continues to have a daunting impact on global health. Fra-1 (FOSL1) plays important roles in oncogenesis in various malignancies. We investigated the expression of Fra-1 in gastric cancer (GC) tissues by qPCR, immunohistochemistry (IHC) and western blot technologies. The results showed that Fra-1 was overexpressed in gastric cancer tissues compared with the adjacent non‑cancerous tissues. To explore the possible mechanism of Fra-1 in GC, we elucidated the effect of Fra-1 in the apoptosis and cell cycle of gastric cancer cells, AGS, and found that a considerable decrease in apoptotic cells and increase of S phase rate were observed for AGS cells with Fra-1 overexpession. We identified and confirmed that Fra-1 affected the expression level of CTTN and EZR in vitro through LC-MS/MS analyses and western blot technology. Furthermore, we found that Fra-1 was correlated with dysregulation PI3K/Akt and p53 signaling pathway in gastric cancer tissues in vitro. Moreover, we found that Fra-1 overexpression affected the expression of PI3K, Akt, MDM2 and p53 in vivo. In summary, our results suggest that Fra-1 is upregulated in gastric cancer tissues and plays its function by affecting the PI3K/Akt and p53 signaling pathway in gastric cancer.

Mina M, Magi S, Jurman G, et al.
Promoter-level expression clustering identifies time development of transcriptional regulatory cascades initiated by ErbB receptors in breast cancer cells.
Sci Rep. 2015; 5:11999 [PubMed] Free Access to Full Article Related Publications
The analysis of CAGE (Cap Analysis of Gene Expression) time-course has been proposed by the FANTOM5 Consortium to extend the understanding of the sequence of events facilitating cell state transition at the level of promoter regulation. To identify the most prominent transcriptional regulations induced by growth factors in human breast cancer, we apply here the Complexity Invariant Dynamic Time Warping motif EnRichment (CIDER) analysis approach to the CAGE time-course datasets of MCF-7 cells stimulated by epidermal growth factor (EGF) or heregulin (HRG). We identify a multi-level cascade of regulations rooted by the Serum Response Factor (SRF) transcription factor, connecting the MAPK-mediated transduction of the HRG stimulus to the negative regulation of the MAPK pathway by the members of the DUSP family phosphatases. The finding confirms the known primary role of FOS and FOSL1, members of AP-1 family, in shaping gene expression in response to HRG induction. Moreover, we identify a new potential regulation of DUSP5 and RARA (known to antagonize the transcriptional regulation induced by the estrogen receptors) by the activity of the AP-1 complex, specific to HRG response. The results indicate that a divergence in AP-1 regulation determines cellular changes of breast cancer cells stimulated by ErbB receptors.

Subramanian D, Bunjobpol W, Sabapathy K
Interplay between TAp73 Protein and Selected Activator Protein-1 (AP-1) Family Members Promotes AP-1 Target Gene Activation and Cellular Growth.
J Biol Chem. 2015; 290(30):18636-49 [PubMed] Free Access to Full Article Related Publications
Unlike p53, which is mutated at a high rate in human cancers, its homologue p73 is not mutated but is often overexpressed, suggesting a possible context-dependent role in growth promotion. Previously, we have shown that co-expression of TAp73 with the proto-oncogene c-Jun can augment cellular growth and potentiate transactivation of activator protein (AP)-1 target genes such as cyclin D1. Here, we provide further mechanistic insights into the cooperative activity between these two transcription factors. Our data show that TAp73-mediated AP-1 target gene transactivation relies on c-Jun dimerization and requires the canonical AP-1 sites on target gene promoters. Interestingly, only selected members of the Fos family of proteins such as c-Fos and Fra1 were found to cooperate with TAp73 in a c-Jun-dependent manner to transactivate AP-1 target promoters. Inducible expression of TAp73 led to the recruitment of these Fos family members to the AP-1 target promoters on which TAp73 was found to be bound near the AP-1 site. Consistent with the binding of TAp73 and AP-1 members on the target promoters in a c-Jun-dependent manner, TAp73 was observed to physically interact with c-Jun specifically at the chromatin via its carboxyl-terminal region. Furthermore, co-expression of c-Fos or Fra1 was able to cooperate with TAp73 in potentiating cellular growth, similarly to c-Jun. These data together suggest that TAp73 plays a vital role in activation of AP-1 target genes via direct binding to c-Jun at the target promoters, leading to enhanced loading of other AP-1 family members, thereby leading to cellular growth.

Li W, Zhang C, Ren A, et al.
Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.
PLoS One. 2015; 10(5):e0126459 [PubMed] Free Access to Full Article Related Publications
The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.

Li B, Wan Z, Huang G, et al.
Mitogen- and stress-activated Kinase 1 mediates Epstein-Barr virus latent membrane protein 1-promoted cell transformation in nasopharyngeal carcinoma through its induction of Fra-1 and c-Jun genes.
BMC Cancer. 2015; 15:390 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase that serves as active link between extracellular signals and the primary response of gene expression. However, the involvement of MSK1 in malignant transformation and cancer development is not well understood. In this study, we aimed to explore the role of MSK1 in Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)-promoted carcinogenesis of nasopharyngeal carcinoma (NPC).
METHODS: The level of MSK1 phosphorylation at Thr581 was detected by the immunohistochemical analysis in NPC tissues and normal nasopharynx tissues, and its correlation with LMP1 was analyzed in NPC tissues and cell lines. Using MSK1 inhibitor H89 or small interfering RNA (siRNA)-MSK1, the effects of MSK1 on LMP1-promoted CNE1 cell proliferation and transformation were evaluated by CCK-8 assay, flow cytometry and focus-forming assay respectively. Furthermore, the regulatory role of MSK1-mediated histone H3 phosphorylation at Ser10 on the promoter activity and expression of Fra-1 or c-Jun was determined by reporter gene assay and western blotting analysis.
RESULTS: Immunohistochemical analysis revealed that the level of MSK1 phosphorylation at Thr581 was significantly higher in the poorly differentiated NPC tissues than that in normal nasopharynx tissues (P < 0.001). Moreover, high level of phosphorylated MSK1 was positively correlated with the expression of LMP1 in NPC tissues (r = 0.393, P = 0.002) and cell lines. MSK1 inhibitor H89 or knockdown of MSK1 by siRNA dramatically suppressed LMP1-promoted CNE1 cell proliferation, which was associated with the induction of cell cycle arrest at G0/G1 phase. In addition, the anchorage-independent growth promoted by LMP1 was blocked in MSK1 knockdown cells. When the activity or expression of MSK1 was inhibited, LMP1-induced promoter activities of Fra-1 and c-Jun as well as their protein levels were greatly reduced. It was found that only H3 WT, but not mutant H3 S10A, dramatically increased LMP1 induction of Fra-1 and c-Jun genes compared with mock cells.
CONCLUSION: Increased MSK1 activity is critically important for LMP1-promoted cell proliferation and transformation in NPC, which may be correlated with its induction of Fra-1 and c-Jun through phosphorylation of histone H3 at Ser10.

Baker EK, Taylor S, Gupte A, et al.
BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells.
Sci Rep. 2015; 5:10120 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ1, I-BET151, I-BET762, exert potent anti-tumour activity against primary and established OS cell lines, mediated by inhibition of BRD4. Strikingly, unlike previous observations in long-term established human OS cell lines, the antiproliferative activity of JQ1 in primary OS cells was driven by the induction of apoptosis, not cell cycle arrest. In further contrast, JQ1 activity in OS was mediated independently of MYC downregulation. We identified that JQ1 suppresses the transcription factor FOSL1 by displacement of BRD4 from its locus. Loss of FOSL1 phenocopied the antiproliferative effects of JQ1, identifying FOSL1 suppression as a potential novel therapeutic approach for OS. As a monotherapy JQ1 demonstrated significant anti-tumour activity in vivo in an OS graft model. Further, combinatorial treatment approaches showed that JQ1 increased the sensitivity of OS cells to doxorubicin and induced potent synergistic activity when rationally combined with CDK inhibitors. The greater level of activity achieved with the combination of BETi with CDK inhibitors demonstrates the efficacy of this combination therapy. Taken together, our studies show that BET inhibitors are a promising new therapeutic for OS.

Kumar K, Raza SS, Knab LM, et al.
GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1.
Sci Rep. 2015; 5:9489 [PubMed] Free Access to Full Article Related Publications
JQ1 and I-BET151 are selective inhibitors of BET bromodomain proteins that have efficacy against a number of different cancers. Since the effectiveness of targeted therapies is often limited by development of resistance, we examined whether it was possible for cancer cells to develop resistance to the BET inhibitor JQ1. Here we show that pancreatic cancer cells developing resistance to JQ1 demonstrate cross-resistance to I-BET151 and insensitivity to BRD4 downregulation. The resistant cells maintain expression of c-MYC, increase expression of JQ1-target genes FOSL1 and HMGA2, and demonstrate evidence of epithelial-mesenchymal transition (EMT). However, reverting EMT fails to sensitize the resistant cells to JQ1 treatment. Importantly, the JQ1-resistant cells remain dependent on c-MYC that now becomes co-regulated by high levels of GLI2. Furthermore, downregulating GLI2 re-sensitizes the resistant cells to JQ1. Overall, these results identify a mechanism by which cancer cells develop resistance to BET inhibitors.

Bian Y, Han J, Kannabiran V, et al.
MEK inhibitor PD-0325901 overcomes resistance to CK2 inhibitor CX-4945 and exhibits anti-tumor activity in head and neck cancer.
Int J Biol Sci. 2015; 11(4):411-22 [PubMed] Free Access to Full Article Related Publications
The serine-threonine kinase CK2 exhibits genomic alterations and aberrant overexpression in human head and neck squamous cell carcinomas (HNSCC). Here, we investigated the effects of CK2 inhibitor CX-4945 in human HNSCC cell lines and xenograft models. The IC50's of CX-4945 for 9 UM-SCC cell lines measured by MTT assay ranged from 3.4-11.9 μM. CX-4945 induced cell cycle arrest and cell death measured by DNA flow cytometry, and inhibited prosurvival mediators phospho-AKT and p-S6 in UM-SCC1 and UM-SCC46 cells. CX-4945 decreased NF-κB and Bcl-XL reporter gene activities in both cell lines, but upregulated proapoptotic TP53 and p21 reporter activities, and induced phospho-ERK, AP-1, and IL-8 activity in UM-SCC1 cells. CX-4945 exhibited modest anti-tumor activity in UM-SCC1 xenografts. Tumor immunostaining revealed significant inhibition of PI3K-Akt-mTOR pathway and increased apoptosis marker TUNEL, but also induced p-ERK, c-JUN, JUNB, FOSL1 and proliferation (Ki67) markers, as a possible resistance mechanism. To overcome the drug resistance, we tested MEK inhibitor PD-0325901 (PD-901), which inhibited ERK-AP-1 activation alone and in combination with CX-4945. PD-901 alone displayed significant anti-tumor effects in vivo, and the combination of PD-901 and CX-4945 slightly enhanced anti-tumor activity when compared with PD-901 alone. Immunostaining of tumor specimens after treatment revealed inhibition of p-AKT S129 and p-AKT T308 by CX-4945, and inhibition of p-ERK T202/204 and AP-1 family member FOSL-1 by PD-901. Our study reveals a drug resistance mechanism mediated by the MEK-ERK-AP-1 pathway in HNSCC. MEK inhibitor PD-0325901 is active in HNSCC resistant to CX-4945, meriting further clinical investigation.

Liu H, Ren G, Wang T, et al.
Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition.
Carcinogenesis. 2015; 36(4):459-68 [PubMed] Free Access to Full Article Related Publications
The pro-inflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment has been suggested to promote development and progression of colorectal cancer (CRC). However, the underlying molecular mechanisms remain elusive. In this study, we demonstrate that fos-related antigen-1 (Fra-1) plays a critical role in IL-6 induced CRC aggressiveness and epithelial-mesenchymal transition (EMT). In CRC cell lines, the expression of Fra-1 gene was found significantly upregulated during IL-6-driven EMT process. The Fra-1 induction occurred at transcriptional level in a manner dependent on signal transducer and activator of transcription 3 (STAT3), during which both phosphorylated and acetylated post-translational modifications were required for STAT3 activation to directly bind to the Fra-1 promoter. Importantly, RNA interference-based attenuation of either STAT3 or Fra-1 prevented IL-6-induced EMT, cell migration and invasion, whereas ectopic expression of Fra-1 markedly reversed the STAT3-knockdown effect and enhanced CRC cell aggressiveness by regulating the expression of EMT-promoting factors (ZEB1, Snail, Slug, MMP-2 and MMP-9). Furthermore, Fra-1 levels were positively correlated with the local invasion depth as well as lymph node and liver metastasis in a total of 229 CRC patients. Intense immunohistochemical staining of Fra-1 was observed at the tumor marginal area adjacent to inflammatory cells and in parallel with IL-6 secretion and STAT3 activation in CRC tissues. Together, this study proposes the existence of an aberrant IL-6/STAT3/Fra-1 signaling axis leading to CRC aggressiveness through EMT induction, which suggests novel therapeutic opportunities for the malignant disease.

Samadani R, Zhang J, Brophy A, et al.
Small-molecule inhibitors of ERK-mediated immediate early gene expression and proliferation of melanoma cells expressing mutated BRaf.
Biochem J. 2015; 467(3):425-38 [PubMed] Free Access to Full Article Related Publications
Constitutive activation of the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are central to regulating the proliferation and survival of many cancer cells. The current inhibitors of ERK1/2 target ATP binding or the catalytic site and are therefore limited in their utility for elucidating the complex biological roles of ERK1/2 through its phosphorylation and regulation of over 100 substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify low-molecular-mass inhibitors that are intended to target ERK1/2 substrate-docking domains and selectively interfere with ERK1/2 regulation of substrate proteins. In the present study, we report the identification and characterization of compounds with a thienyl benzenesulfonate scaffold that were designed to inhibit ERK1/2 substrates containing an F-site or DEF (docking site for ERK, FXF) motif. Experimental evidence shows the compounds inhibit the expression of F-site containing immediate early genes (IEGs) of the Fos family, including c-Fos and Fra1, and transcriptional regulation of the activator protein-1 (AP-1) complex. Moreover, this class of compounds selectively induces apoptosis in melanoma cells containing mutated BRaf and constitutively active ERK1/2 signalling, including melanoma cells that are inherently resistant to clinically relevant kinase inhibitors. These findings represent the identification and initial characterization of a novel class of compounds that inhibit ERK1/2 signalling functions and their potential utility for elucidating ERK1/2 and other signalling events that control the growth and survival of cancer cells containing elevated ERK1/2 activity.

Oliveira-Ferrer L, Kürschner M, Labitzky V, et al.
Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties.
J Cancer Res Clin Oncol. 2015; 141(10):1715-26 [PubMed] Related Publications
PURPOSE: The transcription factor Fos-related antigen-1 (Fra-1) has been described to affect the morphology, motility and invasive potential of breast cancer cells. Since tumor cell adhesion plays an essential role in the metastatic process, especially for extravasation from blood vessels, we investigated the influence of Fra-1 on breast cancer cell interactions with the endothelium.
METHODS: Using Fra-1-overexpressing MCF7 [weakly invasive, estrogen receptor (ER)-positive] and MDA MB231 (strongly invasive, ER-negative) cells, we performed dynamic cell flow adhesion assays on surfaces coated with E-selectin or with human pulmonary microvascular endothelial cells.
RESULTS: We found a significant increased adhesion of Fra-1-overexpressing MCF7 cells to E-selectin but also to activate endothelial cells, whereas the MDA MB231 cell line showed moderate enhanced cell rolling and tethering on both coated surfaces. These different adhesion behaviors corresponded to an up-regulation of various adhesion-related proteins such as CD44 and integrin α5 in Fra-1-overexpressing MCF7 cells measured by microarray analysis and flow cytometry in comparison with no deregulation of key adhesion molecules observed in Fra-1-overexpressing MDA MB231 cells. In line with these results and based on cDNA microarray data of breast cancer patients (n = 197), high Fra-1 expression significantly correlates with shorter overall survival and higher rate of lung metastasis in ER-positive breast cancer patients (n = 130), but has no impact on the prognosis of patients with ER-negative tumors.
CONCLUSION: Thus, in addition to its pro-invasive and pro-migratory effect, Fra-1 might influence the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells under flow conditions.

Xiao S, Zhou Y, Yi W, et al.
Fra-1 is downregulated in cervical cancer tissues and promotes cervical cancer cell apoptosis by p53 signaling pathway in vitro.
Int J Oncol. 2015; 46(4):1677-84 [PubMed] Related Publications
Cervical cancer is a potentially preventable disease; however, it is the third most commonly diagnosed cancer and the fourth leading cause of cancer deaths in women worldwide. Cervical cancer is thought to develop through a multistep process involving virus, tumor suppressor genes, proto-oncogenes and immunological factors. It is known that human papillomavirus (HPV) infection is necessary but insufficient to cause malignancy. At present, the etiology of cervical carcinoma remains poorly understood. In this study, we found that the expression of FOS-like antigen-1 (Fra-1) gene was downregulated in cervical cancer compared with the adjacent non-cancerous tissues by RT-qPCR, immunohistochemistry (IHC) and western blotting techniques. To uncover the effect of Fra-1 on cervical cancer, we tested and confirmed that Fra-1 significantly inhibited the proliferation of HeLa cells by MMT assays in vitro. At the same time, overexpression of Fra-1 promoted apoptosis of HeLa cells. To explore the possible mechanism of Fra-1 in cervical cancer, we tested the expression levels of key molecules in p53 signaling pathway by western blotting technology. The results showed that p53 was downregulated in cervical cancer compared with the adjacent non-cancerous tissues, but MDM2 proto-oncogene, E3 ubiquitin protein ligase (MDM2) was upregulated in cervical cancer. In vitro, the p53 was upregulated and MDM2 was downregulated in HeLa cells with Fra-1 overexpression. In summary, our results suggested that Fra-1 expression is low in cervical cancer tissues and promotes apoptosis of cervical cancer cells by p53 signaling pathway.

Zubor P, Hatok J, Moricova P, et al.
Gene expression abnormalities in histologically normal breast epithelium from patients with luminal type of breast cancer.
Mol Biol Rep. 2015; 42(5):977-88 [PubMed] Related Publications
The gene expression profile of breast cancer has been described as a great breakthrough on the way to comprehend differences in cancer origin, behavior and therapy. However, gene expression profile in histologically normal epithelium (HNEpi) which could harbor genetic abnormalities predisposing breast tissue to develop malignancy was minor scope for scientists in the past. Thus, we aimed to analyze gene expressions in HNEpi and breast cancer tissue (BCTis) in order to establish its value as potential diagnostic marker for cancer development. We evaluated a panel of disease-specific genes in luminal type (A/B) of breast cancer and tumor surrounding HNEpi by qRT-PCR Array in 32 microdissected samples. There was 20.2 and 2.4% deregulation rate in genes with at least 2-fold or 5-fold over-expression between luminal (A/B) type breast carcinomas and tumor surrounding HNEpi, respectively. The high-grade luminal carcinomas showed higher number of deregulated genes compared to low-grade cases (50.6 vs. 23.8% with at least 2-fold deregulation rate). The main overexpressed genes in HNEpi were KLK5, SCGB1D2, GSN, EGFR and NGFR. The significant differences in gene expression between BCTis and HNEpi samples were revealed for BAG1, C3, CCNA2, CD44, FGF1, FOSL1, ID2, IL6R, NGFB, NGFR, PAPPA, PLAU, SERPINB5, THBS1 and TP53 gene (p < 0.05) and BCL2L2, CTSB, ITGB4, JUN, KIT, KLF5, SCGB1D2, SCGB2A1, SERPINE1 (p < 0.01), and EGFR, GABRP, GSN, MAP2K7 and THBS2 (p < 0.001), and GSN, KLK5 (p < 0.0001). The ontological gene analyses revealed high deregulations in gene group directly associated with breast cancer prognosis and origin.

Dhillon AS, Tulchinsky E
FRA-1 as a driver of tumour heterogeneity: a nexus between oncogenes and embryonic signalling pathways in cancer.
Oncogene. 2015; 34(34):4421-8 [PubMed] Free Access to Full Article Related Publications
Tumour heterogeneity is a major factor undermining the success of therapies targeting metastatic cancer. Two major theories are thought to explain the phenomenon of heterogeneity in cancer--clonal evolution and cell plasticity. In this review, we examine a growing body of work implicating the transcription factor FOS-related antigen 1 (FRA-1) as a central node in tumour cell plasticity networks, and discuss mechanisms regulating its activity in cancer cells. We also discuss evidence from the FRA-1 perspective supporting the notion that clonal selection and cell plasticity represent two sides of the same coin. We propose that FRA-1-overexpressing clones featuring high plasticity undergo positive selection during consecutive stages of multistep tumour progression. This model underscores a potential mechanism through which tumour cells retaining elevated levels of plasticity acquire a selective advantage over other clonal populations within a tumour.

Bakiri L, Macho-Maschler S, Custic I, et al.
Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression.
Cell Death Differ. 2015; 22(2):336-50 [PubMed] Free Access to Full Article Related Publications
Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models.

Moquet-Torcy G, Tolza C, Piechaczyk M, Jariel-Encontre I
Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer.
Nucleic Acids Res. 2014; 42(17):11011-24 [PubMed] Free Access to Full Article Related Publications
Plau codes for the urokinase-type plasminogen activator (uPA), critical in cancer metastasis. While the mechanisms driving its overexpression in tumorigenic processes are unknown, it is regulated by the AP-1 transcriptional complex in diverse situations. The AP-1 component Fra-1 being overexpressed in aggressive breast cancers, we have addressed its role in the overexpression of Plau in the highly metastatic breast cancer model cell line MDA-MB231 using ChIP, pharmacological and RNAi approaches. Plau transcription appears controlled by 2 AP-1 enhancers located -1.9 (ABR-1.9) and -4.1 kb (ABR-4.1) upstream of the transcription start site (TSS) of the uPA-coding mRNA, Plau-001, that bind Fra-1. Surprisingly, RNA Pol II is not recruited only at the Plau-001 TSS but also upstream in the ABR-1.9 and ABR-4.1 region. Most Pol II molecules transcribe short and unstable RNAs while tracking down toward the TSS, where there are converted into Plau-001 mRNA-productive species. Moreover, a minority of Pol II molecules transcribes a low abundance mRNA of unknown function called Plau-004 from the ABR-1.9 domain, whose expression is tempered by Fra-1. Thus, we unveil a heretofore-unsuspected transcriptional complexity at Plau in a reference metastatic breast cancer cell line with pleiotropic effects for Fra-1, providing novel information on AP-1 transcriptional action.

Antal O, Hackler L, Shen J, et al.
Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: cellular, biochemical and gene expression analysis.
Lipids Health Dis. 2014; 13:142 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Based on previous observations a potential resort in the therapy of the particularly radioresistant glioma would be its treatment with unsaturated fatty acids (UFAs) combined with irradiation.
METHODS: We evaluated the effect of different UFAs (arachidonic acid (AA), docosahexaenoic acid (DHA), gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and oleic acid (OA)) on human U87 MG glioma cell line by classical biochemical end-point assays, impedance-based, real-time cellular and holographic microscopic analysis. We further analyzed AA, DHA, and GLA at morphological, gene and miRNA expression level.
RESULTS: Corresponding to LDH-, MTS assays and real-time cytoxicity profiles AA, DHA, and GLA enhanced the radio sensitivity of glioma cells. The collective application of polyunsaturated fatty acids (PUFAs) and irradiation significantly changed the expression of EGR1, TNF-α, NOTCH1, c-MYC, TP53, HMOX1, AKR1C1, NQO1, while up-regulation of GADD45A, EGR1, GRP78, DDIT3, c-MYC, FOSL1 were recorded both in response to PUFA treatment or irradiation alone. Among the analyzed miRNAs miR-146 and miR-181a were induced by DHA treatment. Overexpression of miR-146 was also detected by combined treatment of GLA and irradiation.
CONCLUSIONS: Because PUFAs increased the radio responsiveness of glioma cells as assessed by biochemical and cellular assays, they might increase the therapeutic efficacy of radiation in treatment of gliomas. We demonstrated that treatment with DHA, AA and GLA as adjunct to irradiation up-regulated the expression of oxidative-stress and endoplasmic reticulum stress related genes, and affected NOTCH1 expression, which could explain their additive effects.

Risolino M, Mandia N, Iavarone F, et al.
Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β-SMAD3 pathway in non-small cell lung adenocarcinoma.
Proc Natl Acad Sci U S A. 2014; 111(36):E3775-84 [PubMed] Free Access to Full Article Related Publications
Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.

Godde NJ, Sheridan JM, Smith LK, et al.
Scribble modulates the MAPK/Fra1 pathway to disrupt luminal and ductal integrity and suppress tumour formation in the mammary gland.
PLoS Genet. 2014; 10(5):e1004323 [PubMed] Free Access to Full Article Related Publications
Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland. Loss of polarity and the deregulation of these processes are critical events in malignant progression but precisely how and at which stage polarity loss impacts on mammary development and tumourigenesis is unclear. Scrib is a core polarity regulator and tumour suppressor gene however to date our understanding of Scrib function in the mammary gland has been limited to cell culture and transplantation studies of cell lines. Utilizing a conditional mouse model of Scrib loss we report for the first time that Scrib is essential for mammary duct morphogenesis, mammary progenitor cell fate and maintenance, and we demonstrate a critical and specific role for Scribble in the control of the early steps of breast cancer progression. In particular, Scrib-deficiency significantly induced Fra1 expression and basal progenitor clonogenicity, which resulted in fully penetrant ductal hyperplasia characterized by high cell turnover, MAPK hyperactivity, frank polarity loss with mixing of apical and basolateral membrane constituents and expansion of atypical luminal cells. We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis. Restoring MAPK/Fra1 to baseline levels prevented Scrib-hyperplasia, whereas persistent Scrib deficiency induced alveolar hyperplasia and increased the incidence, onset and grade of mammary tumours. These findings, based on a definitive genetic mouse model provide fundamental insights into mammary duct maturation and homeostasis and reveal that Scrib loss activates a MAPK/Fra1 pathway that alters mammary progenitor activity to drive premalignancy and accelerate tumour progression.

Zhao C, Qiao Y, Jonsson P, et al.
Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.
Cancer Res. 2014; 74(14):3983-94 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.

Diesch J, Sanij E, Gilan O, et al.
Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells.
PLoS One. 2014; 9(3):e88950 [PubMed] Free Access to Full Article Related Publications
Tumor invasion and metastasis involves complex remodeling of gene expression programs governing epithelial homeostasis. Mutational activation of the RAS-ERK is a frequent occurrence in many cancers and has been shown to drive overexpression of the AP-1 family transcription factor FRA1, a potent regulator of migration and invasion in a variety of tumor cell types. However, the nature of FRA1 transcriptional targets and the molecular pathways through which they promote tumor progression remain poorly understood. We found that FRA1 was strongly expressed in tumor cells at the invasive front of human colorectal cancers (CRCs), and that its depletion suppressed mesenchymal-like features in CRC cells in vitro. Genome-wide analysis of FRA1 chromatin occupancy and transcriptional regulation identified epithelial-mesenchymal transition (EMT)-related genes as a major class of direct FRA1 targets in CRC cells. Expression of the pro-mesenchymal subset of these genes predicted adverse outcomes in CRC patients, and involved FRA-1-dependent regulation and cooperation with TGFβ signaling pathway. Our findings reveal an unexpectedly widespread and direct role for FRA1 in control of epithelial-mesenchymal plasticity in CRC cells, and suggest that FRA1 plays an important role in mediating cross talk between oncogenic RAS-ERK and TGFβ signaling networks during tumor progression.

Gilan O, Diesch J, Amalia M, et al.
PR55α-containing protein phosphatase 2A complexes promote cancer cell migration and invasion through regulation of AP-1 transcriptional activity.
Oncogene. 2015; 34(10):1333-9 [PubMed] Related Publications
The proto-oncogene c-Jun is a component of activator protein-1 (AP-1) transcription factor complexes that regulates processes essential for embryonic development, tissue homeostasis and malignant transformation. Induction of gene expression by c-Jun involves stimulation of its transactivation ability and upregulation of DNA binding capacity. While it is well established that the former requires JNK-mediated phosphorylation of S63/S73, the mechanism(s) through which binding of c-Jun to its endogenous target genes is regulated remains poorly characterized. Here we show that interaction of c-Jun with chromatin is positively regulated by protein phosphatase 2A (PP2A) complexes targeted to c-Jun by the PR55α regulatory subunit. PR55α-PP2A specifically dephosphorylates T239 of c-Jun, promoting its binding to genes regulating tumour cell migration and invasion. PR55α-PP2A also enhanced transcription of these genes, without affecting phosphorylation of c-Jun on S63. These findings suggest a critical role for interplay between JNK and PP2A pathways determining the functional activity of c-Jun/AP-1 in tumour cells.

Xiao S, Zhou Y, Jiang J, et al.
CD44 affects the expression level of FOS‑like antigen 1 in cervical cancer tissues.
Mol Med Rep. 2014; 9(5):1667-74 [PubMed] Related Publications
Cervical carcinoma is the second most prevalent type of malignancy in females worldwide. The crucial etiological factors involved in the development of cervical carcinoma include infection with the papillomavirus, and the structural or functional mutation of oncogenes and tumor suppressor genes. CD44 refers to a multifunctional family of type I transmembrane proteins. These proteins have been implicated in numerous biological processes, including cell adhesion, cell migration and metastasis. The present study examined the differences in the expression levels of ATP-binding cassette sub-family G member 2, CD24, CD44, CD133, cytokeratin (CK) 14 and CK19 between cervical cancer tissues and corresponding normal non-tumor tissues by flow cytometry. Then, the CD44+ or CD44‑ cells from cervical cancer tissues were sorted for identification and confirmation of differential expression by flow cytometry. The results demonstrated that the expression level of CD44 in cervical cancer tissues was higher than in the corresponding non-tumor normal tissues (t=3.12; P=0.0102). Compared with the CD44‑ cells, the FOS-like antigen 1 (Fra-1), nestin, nuclear receptor subfamily 4, group A, member 2, OCT4 and p63 genes were highly expressed in CD44+ cells. The fold changes were 3.55, 3.55, 2.46, 2.87 and 2.56, respectively (P<0.05). However, BMI1 polycomb ring finger oncogene, ck5, tumor protein p53 and lactotransferrin genes exhibited low expression levels in CD44+ cells. It was verified by western blot analysis and flow cytometry that Fra-1 was highly expressed in CD44+ cells. Fra-1 was a potential target of miR-19a and miR-19b. The expression of miR-19a and miR-19b was downregulated by ~50% in CD44+ cells compared with CD44‑ cells. These findings suggested that CD44 dysregulated the activation of the Fra‑1 gene. The interaction of Fra-1 and CD44 may therefore be important in cervical carcinoma.

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