The ETS Gene ETV4 Is Required for Anchorage-Independent Growth and a Cell Proliferation Gene Expression Program in PC3 Prostate Cells

Hollenhorst, Peter C.; Paul, Litty; Ferris, Mary W.; Graves, Barbara J.

doi:10.1177/1947601910395578

Cited by 53 publications

(80 citation statements)

References 36 publications

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“…2). Both of these factors have been implicated in the physiology of cancer and development: polyomavirus enhancer activator 3 (PEA3) plays critical roles in invasion, migration, and proliferation of cancer cells, [28][29][30] and epithelium-specific ETS transcription factor-1 (ESE-1) mRNA is upregulated at least 6-fold after mouse EC cells differentiate. 31) Together with the previously published findings, our expression data suggest that the ETS factors PEA3 and ESE-1 play important roles in pluripotent and tumorigenic EC cells.…”

Section: Resultsmentioning

confidence: 99%

Differential Expression of ETS Family Transcription Factors in NCCIT Human Embryonic Carcinoma Cells upon Retinoic Acid-Induced Differentiation

Park

et al. 2014

Biological & Pharmaceutical Bulletin

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E26 transformation-specific (ETS) transcription factors play important roles in normal and tumorigenic processes during development, differentiation, homeostasis, proliferation, and apoptosis. To identify critical ETS factor(s) in germ cell-derived cancer cells, we examined the expression patterns of the 27 ETS transcription factors in naive and differentiated NCCIT human embryonic carcinoma cells, which exhibit both pluripotent and tumorigenic characteristics. Overall, expression of ETS factors was relatively low in NCCIT cells. Among the 27 ETS factors, polyomavirus enhancer activator 3 (PEA3) and epithelium-specific ETS transcription factor-1 (ESE-1) exhibited the most significant changes in their expression levels. Western blot analysis confirmed these patterns, revealing reduced levels of PEA3 protein and elevated levels of ESE-1 protein in differentiated cells. PEA3 increased the proportion of cells in S-phase and promoted cell growth, whereas ESE-1 reduced proliferation potential. These data suggest that PEA3 and ESE-1 may play important roles in pluripotent and tumorigenic embryonic carcinoma cells. These findings contribute to our understanding of the functions of oncogenic ETS factors in germ cell-derived stem cells during processes related to tumorigenesis and pluripotency.

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Section: Resultsmentioning

confidence: 99%

Differential Expression of ETS Family Transcription Factors in NCCIT Human Embryonic Carcinoma Cells upon Retinoic Acid-Induced Differentiation

Park

et al. 2014

Biological & Pharmaceutical Bulletin

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“…ETV genes (i.e., members of the PEA3 subfamily of ETS genes) have previously been implicated as transcriptional regulators of cancer invasion and metastasis in various cancer types, and several of their targets include genes associated with metastatic dissemination (51,52,62,63). Furthermore, it has previously been proposed that ETV4 may be particularly relevant for prostate cancer progression, because it is robustly up-regulated in PC3 human prostate cancer cells, and its depletion in these cells impairs their anchorageindependent growth in cell culture (50). Interestingly, our analysis of ETV4 target gene activation in human prostate cancer has revealed that ETV4 is preferentially correlated with PI3-kinase and Ras signaling in bone metastases compared with lymph node metastases (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…7 A and B; SI Appendix and Datasets S4 and S5). Notably, these ETS transcription factors have been previously implicated in mediating Ras signaling in prostate (49,50) and other cancers (51,52), as well as in regulation of EMT markers, including Snail (53,54).…”

Section: Activation Of Etv4 By Pi3-kinase and Ras Signaling In Metastmentioning

confidence: 99%

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Aytés

Mitrofanova

Kinkade³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

129

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Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer. M etastasis is a highly inefficient process that involves multiple steps, including invasion of local stroma, intravasation into the bloodstream and/or lymphatic system, and extravasation into a secondary tissue, which is thought to arise as a consequence of multiple molecular/epigenetic alterations in tumor cells, as well as in the microenvironment of metastatic sites (1-4). Nonetheless, despite its inefficiency, most cancer deaths are due to metastases and our current inability to treat them once they arise. In particular, in prostate cancer, the locally invasive disease has a nearly 100% survival rate, whereas metastatic prostate cancer is very often lethal (5).Recent analyses have identified key molecular pathways that are frequently dysregulated during prostate cancer progression, as a consequence of copy number alterations, chromosomal rearrangements, and other aberrant genetic/epigenetic events (6-10). For example, loss of chromosomal region 8p21 and coincident haploinsufficiency for the NKX3.1 homeobox gene occurs frequently in precursor lesions known as prostatic intraepithelial neoplasia (PIN) and are associated with prostate cancer initiation (11,12). Another early event in prostate tumorigenesis is the formation of the TMPRSS2-ERG rearrangement, which fuses the transmembrane protease TMPRSS2 promoter with the coding region of the ETS transcription factor ERG (13, 14). The TMPRSS2-ERG fusion is highly prevalent in prostate cancer and is associated with disease out...

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“…Androgensignaling brings these two genes into proximity, thus inducing their fusion (313). Altogether, the untranslated 5'UTR region of gene TMPRSS2 (21q22) may fuse with ERG (21q22), ETV1 (7p21), SLC45A3 9 (solute carrier gene) and with HERVK, the human endogenous retrovirus gene, that in extravillous cytotrophoblasts exerts immunosuppressive properties in the defense of the fetus (314,315) (318).…”

Section: Ebvmentioning

confidence: 99%

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

Sinkovics

2011

Int J Oncol

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Abstract. In some inflammasomes tumor cells are generated. The internal environment of the inflammasome is conducive to the induction of malignant transformation. Epigenetic changes initiate this process. The subverted stromal connective tissue cells act to promote and sustain the process of malignant trans formation. In its early stages, the premalignant cells depend on paracrine circuitries for the reception of growth factors. The ligands are derived from the connective tissue, and the receptors are expressed on the recipient premalignant cells. The initial events are not a direct attack on the protooncogenes, and thus it may be entirely reversible. Epigenetic processes of hypermethylation of the genes at the promoters of tumor suppressor genes (to silence them), and deacetylation of the histones aimed at the promoters of protooncogenes (to activate them) are ongoing. A large number of short RNA sequences (interfering, micro, short hairpin, noncoding RNAs) silence tumor suppressor genes, by neutralizing their mRNAs. In a serial sequence oncogenes undergo amplifications, pointmutations, translocations and fusions. In its earliest stage, the process is reversible by demethylation of the silenced suppressor gene promoters (to reactivate them), or reacetylation of the histones of the oncogene promoters, thus deactivating them. The external administration of histone deacetylase inhibitors usually leads to the restoration of histone acetylation. In time, the uncorrected processes solidify into constitutive and irreversible gene mutations. Some of the pathogens inducing inflammations with consquential malignant transformation contain oncogenic gene sequences (papilloma viruses, EpsteinBarr virus, Kaposi's sarcomaassociated herpesvirus, hepatitis B and C viruses, Merkel cell polyoma virus, Helicobacter pylori, enterotoxigenic Bacteroides fragilis). These induced malignancies may be multifocal. Other pathogens are devoid of any known oncogenic genomic sequences (mycoplasma vavcarcinogenesis, chlamydia MALTlymphoma genesis). In these cases the host's inflammatory reactions induce the malignant transformation in serial sequences of gene alterations initiated by hypoxia and reactive oxygen and nitrogen species generation. Carcinogenic intrinsic inflammatory processes endogenously initiated without a pathogen are recognized. Chronic inflammatory processes signal the RNA/DNA complex. In response, the DNA may revert into its ancient primordial 'immortal' format, which the clinics recognize as 'oncogenesis'. The DNA remains the ultimate master of bioengineering in order to sustain life. A discussion on the most versatile and resistant primordial RNA/ DNA complex and the pre, proto, and unicellular world in which they coexisted is included. Contents1. Pathogens without oncogenic genomic sequences activating cellular oncogenes 2. The inflammasome 3. Tumor cell colonies generated in the inflammasomes 4. Pathogens with potentially oncogenic genomic sequences 5. Mechanisms of inflammatory carcinogenesis Pathogens without oncogenic...

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The ETS Gene ETV4 Is Required for Anchorage-Independent Growth and a Cell Proliferation Gene Expression Program in PC3 Prostate Cells

Cited by 53 publications

References 36 publications

Differential Expression of ETS Family Transcription Factors in NCCIT Human Embryonic Carcinoma Cells upon Retinoic Acid-Induced Differentiation

Differential Expression of ETS Family Transcription Factors in NCCIT Human Embryonic Carcinoma Cells upon Retinoic Acid-Induced Differentiation

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

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