The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells

Adamo, Patricia; Porazinski, Sean; Rajatileka, Shavanthi; Jumbe, Samantha L.; Hagen, R; Cheung, Man-Kim; Wilson, Ian; Ladomery, Michael

doi:10.3892/ol.2017.6841

Cited by 8 publications

(9 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Possible explanations for this relationship include the known interaction of PNUTS with PTEN [10]. ERG expression suppresses the transcription of PTEN [45]. The significant association between androgen receptor and PNUTS expression fits well with earlier reports demonstrating interactions between the PNUTS target PP1 and the androgen receptor.…”

Section: Discussionsupporting

confidence: 88%

Upregulation of Phosphatase 1 Nuclear-Targeting Subunit (PNUTS) Is an Independent Predictor of Poor Prognosis in Prostate Cancer

et al. 2020

View full text Add to dashboard Cite

Protein phosphatase 1 nuclear-targeting subunit (PNUTS) is ubiquitously expressed and associates with PTEN and protein phosphatase 1 (PP1) to control its activity. The role of PNUTS overexpression has hardly been studied in cancer. In this study, we used immunohistochemistry to quantitate PNUTS expression on a tissue microarray containing 17,747 clinical prostate cancer specimens. As compared to normal prostate epithelium, PNUTS expression was often higher in cancer. Among 12,235 interpretable tumors, PNUTS staining was negative in 21%, weak in 34%, moderate in 35%, and strong in 10% of cases. High PNUTS expression was associated with higher tumor stage, classical and quantitative Gleason grade, nodal stage, surgical margin, Ki67 labeling index, and early biochemical recurrence (p<0.0001 each). PNUTS expression proved to be a moderate prognostic parameter with a maximal univariable Cox proportional hazard for PSA recurrence-free survival of 2.21 compared with 5.91 for Gleason grading. It was independent from established prognostic parameters in multivariable analysis. Comparison with molecular data available from earlier studies using the same TMA identified associations between high PNUTS expression and elevated androgen receptor expression (p<0.0001), presence of TMPRSS2:ERG fusion (p<0.0001), and 8 of 11 chromosomal deletions (3p13, 5q21, 8p21, 10q23, 12p13, 13q14, 16q24, and 17p13; p<0.05 each). Particularly strong associations with PTEN and 12p13 deletions (p<0.0001 each) may indicate a functional relationship, which has already been established for PNUTS and PTEN. PNUTS had no additional role on outcome in PTEN-deleted cancers. In conclusion, the results of our study identify high PNUTS protein levels as a predictor of poor prognosis possibly linked to increased levels of genomic instability. PNUTS measurement, either alone or in combination, might be of clinical utility in prostate cancers.

show abstract

Section: Discussionsupporting

confidence: 88%

Upregulation of Phosphatase 1 Nuclear-Targeting Subunit (PNUTS) Is an Independent Predictor of Poor Prognosis in Prostate Cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…4c, d). We have previously demonstrated that ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells 9 . In support of this, in parallel to ERG reduction, we noted an increase in PTEN protein expression in the E43′ SSO-treated sample ( Supplementary Fig.…”

Section: Ssos Reduce Erg Protein Levels In Patient-derived Prostate Cmentioning

confidence: 99%

“…The list of oncologically significant transcriptional targets of ERG is growing. These now include the Wnt receptor Frizzled 8 (FZD8) 8 , the tumour suppressor phosphatase and tensin homologue (PTEN) 9 , and the α1 and β1 subunits of soluble guanylyl cycles (GUCY1A3 and GUCY1B3) 10 , the latter indicating that TMPRSS2:ERG can activate NO-cGMP signalling in PCa.…”

Section: Introductionmentioning

confidence: 99%

Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

Hobson

Perry

et al. 2020

Br J Cancer

Self Cite

View full text Add to dashboard Cite

BACKGROUND: The ERG oncogene is activated in 50% of prostate cancers. We have designed morpholino-based oligonucleotides that target the ERG oncogene by inducing skipping of exon 4. METHODS: We designed antisense splice-switching morpholino oligonucleotides (SSOs) that target exon 4. We tested their efficacy in ERG-positive VCaP prostate cancer and MG63 osteosarcoma cell lines. We measured their effect on ERG expression, cell proliferation, migration and apoptosis in cell lines, xenografts and a radical prostatectomy sample. RESULTS: SSOs induced exon 4 skipping, reducing ERG levels up to 96 hours following transfection. SSO-induced ERG reduction decreased cell proliferation, cell migration and increased apoptosis. We observed a reduction in cyclin D1, c-Myc, β-catenin and a marker of activated Wnt signalling, p-LRP6. SSOs reduced the growth of MG63 xenografts in mice. We also demonstrated that the SSOs cause a reduction in ERG expression in a patient-derived radical prostatectomy sample ex vivo. CONCLUSIONS: We have successfully tested morpholino-based SSOs that cause a marked reduction in ERG expression, resulting in decreased cell proliferation, a reduced migratory phenotype and increased apoptosis. Our initial tests on mouse xenografts and a human prostate cancer radical prostatectomy specimen indicate that SSOs can be effective for ERG oncogene targeting in vivo.

show abstract

“…E26 transformation specific (ETS) related genes (ERGs) also play significant roles in cancer metastasis, along with roles in inflammation, migration, and invasion alongside angiogenesis [59]. Chromosomal translocation and amplification cause increased ETS signaling, which enhances tumorigenesis [60].…”

Section: Role Of Oncogenic Transcription Factors In Cancer Metastasismentioning

confidence: 99%

“…Chromosomal translocation and amplification cause increased ETS signaling, which enhances tumorigenesis [60]. In the specific case of ERG, its activation and overexpression are often associated with prostate cancer because it inactivates phosphatase and tensin homologue, a tumor suppressor gene [59].…”

Section: Role Of Oncogenic Transcription Factors In Cancer Metastasismentioning

confidence: 99%

The Role of Transcription Factors in Cancer Angiogenesis and Metastasis

Gu¹,

Wang²,

Madu³

et al. 2020

NACS

View full text Add to dashboard Cite

The oncogenic transcription factor ERG represses the transcription of the tumour suppressor gene PTEN in prostate cancer cells

Cited by 8 publications

References 28 publications

Upregulation of Phosphatase 1 Nuclear-Targeting Subunit (PNUTS) Is an Independent Predictor of Poor Prognosis in Prostate Cancer

Upregulation of Phosphatase 1 Nuclear-Targeting Subunit (PNUTS) Is an Independent Predictor of Poor Prognosis in Prostate Cancer

Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

The Role of Transcription Factors in Cancer Angiogenesis and Metastasis

Contact Info

Product

Resources

About