Oncogenic ETS Factors in Prostate Cancer

Nicholas, Taylor R.; Strittmatter, Brady G.; Hollenhorst, Peter C.

doi:10.1007/978-3-030-32656-2_18

Cited by 34 publications

(31 citation statements)

References 192 publications

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“…These observations suggest that the role of ETV4 in cancer is cell-type and tissue-dependent; it behaves as an oncogene in prostate and breast cells (and in many others tissues) [ 69 ], whereas it acts as a tumor suppressor gene in osteosarcoma [ 68 ] and in cervical cells [ 62 ]. This apparent discrepancy could be explained by the fact that different cell types express different tissue-specific factors that, in turn, may influence the role of ETV4 as it happens for others ETS transcription factors [ 5 , 70 ].…”

Section: Discussionmentioning

confidence: 99%

“…In almost half of patients with prostate cancer, the tumor carries one of recurrent translocations that place one of the genes from the ETS family ( ERG, ETV1, ETV4, ETV5, FLI1 ) downstream to the promoter of a gene active in the prostate, with consequent aberrant overexpression of the respective ETS gene [ 2 – 5 ]. The role of the ETS genes in prostate carcinogenesis has been investigated in transgenic mice models with a prostate-specific ETS overexpression [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

et al. 2020

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Background: ETV4 is one of the ETS proteins overexpressed in prostate cancer (PC) as a result of recurrent chromosomal translocations. In human prostate cell lines, ETV4 promotes migration, invasion, and proliferation; however, its role in PC has been unclear. In this study, we have explored the effects of ETV4 expression in the prostate in a novel transgenic mouse model. Methods: We have created a mouse model with prostate-specific expression of ETV4 (ETV4 mice). By histochemical and molecular analysis, we have investigated in these engineered mice the expression of p21, p27, and p53. The implications of our in vivo findings have been further investigated in human cells lines by chromatin-immunoprecipitation (ChIP) and luciferase assays. Results: ETV4 mice, from two independent transgenic lines, have increased cell proliferation in their prostate and two-thirds of them, by the age of 10 months, developed mouse prostatic intraepithelial neoplasia (mPIN). In these mice, cdkn1a and its p21 protein product were reduced compared to controls; p27 protein was also reduced. By ChIP assay in human prostate cell lines, we show that ETV4 binds to a specific site (-704/-696 bp upstream of the transcription start) in the CDKN1A promoter that was proven, by luciferase assay, to be functionally competent. ETV4 further controls CDKN1A expression by downregulating p53 protein: this reduction of p53 was confirmed in vivo in ETV4 mice. Conclusions: ETV4 overexpression results in the development of mPIN but not in progression to cancer. ETV4 increases prostate cell proliferation through multiple mechanisms, including downregulation of CDKN1A and its p21 protein product: this in turn is mediated through direct binding of ETV4 to the CDKN1A promoter and through the ETV4-mediated decrease of p53. This multi-faceted role of ETV4 in prostate cancer makes it a potential target for novel therapeutic approaches that could be explored in this ETV4 transgenic model.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

et al. 2020

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“…Site-directed mutagenesis studies identified a hydrophobic pocket that plays a critical role for binding the TAD of the VP16 protein encoded by Herpes virus, as well as the TADs of cellular transcription factors, such as the ‘Ets-related molecule’ (ETV5; also known as ERM; ( Figure 1 a–c)). ETV5 has been implicated in controlling aspects of cell differentiation and proliferation, immune response, apoptosis and cancer [ 18 ]. One of the TADs of ETV5 (AD1; Figure 1 a) has been narrowed down to a short motif located near the N-terminus of the protein (ETV5 38–68 ; Supplementary Materials Figure 1 ) [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator

Jeffery

Weinzierl

2020

Biomolecules

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The human mediator subunit MED25 acts as a coactivator that binds the transcriptional activation domains (TADs) present in various cellular and viral gene-specific transcription factors. Previous studies, including on NMR measurements and site-directed mutagenesis, have only yielded low-resolution models that are difficult to refine further by experimental means. Here, we apply computational molecular dynamics simulations to study the interactions of two different TADs from the human transcription factor ETV5 (ERM) and herpes virus VP16-H1 with MED25. Like other well-studied coactivator-TAD complexes, the interactions of these intrinsically disordered domains with the coactivator surface are temporary and highly dynamic (‘fuzzy’). Due to the fact that the MED25 TAD-binding region is organized as an elongated cleft, we specifically asked whether these TADs are capable of binding in either orientation and how this could be achieved structurally and energetically. The binding of both the ETV5 and VP16-TADs in either orientation appears to be possible but occurs in a conformationally distinct manner and utilizes different sets of hydrophobic residues present in the TADs to drive the interactions. We propose that MED25 and at least a subset of human TADs specifically evolved a redundant set of molecular interaction patterns to allow binding to particular coactivators without major prior spatial constraints.

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“…The ETS transcription factor family is composed of 28 members, some of which are normally expressed in the prostate and control healthy function [ 5 ]. However, rearrangement-induced expression of the specific ETS factors ERG, ETV1, ETV4, and ETV5 drive an oncogenic gene expression program in this ectopic setting [ 4 , 6 – 8 ]. ETS factors are classified by the presence of a conserved ETS DNA binding domain, so targeting the ETS factor-DNA interaction will likely impact endogenous ETS factors, some of which act as tumor suppressors [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, rearrangement-induced expression of the specific ETS factors ERG, ETV1, ETV4, and ETV5 drive an oncogenic gene expression program in this ectopic setting [ 4 , 6 – 8 ]. ETS factors are classified by the presence of a conserved ETS DNA binding domain, so targeting the ETS factor-DNA interaction will likely impact endogenous ETS factors, some of which act as tumor suppressors [ 6 ]. Outside of the structured ETS domain, ETS factors are largely disordered, posing a challenge to rational structure-based therapeutic design.…”

Section: Introductionmentioning

confidence: 99%

A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS

et al. 2020

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Aberrant expression of the transcription factor ERG is a key driving event in approximately one-half of all of prostate cancers. Lacking an enzymatic pocket and mainly disordered, the structure of ERG is difficult to exploit for therapeutic design. We recently identified EWS as a specific interacting partner of ERG that is required for oncogenic function. In this study, we aimed to target this specific protein-protein interaction with small molecules. A high-throughput screening (HTS) strategy was implemented to identify potential protein-protein interaction inhibitors. Secondary assays verified the function of several hit compounds, and one lead compound inhibited ERG-mediated phenotypes in prostate cells. This is the first study aimed at targeting the ERG-EWS protein-protein interaction for the development of a small molecule-based prostate cancer therapy.

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Oncogenic ETS Factors in Prostate Cancer

Cited by 34 publications

References 192 publications

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator

A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS

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Oncogenic ETS Factors in Prostate Cancer

Cited by 34 publications

References 192 publications

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21

Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator

­­A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS

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A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS