TY - JOUR
T1 - Relationship between ETS Transcription Factor ETV1 and TGF-β-regulated SMAD Proteins in Prostate Cancer
AU - Oh, Sangphil
AU - Shin, Sook
AU - Song, Hoogeun
AU - Grande, Joseph P.
AU - Janknecht, Ralf
N1 - Funding Information:
The Stephenson Cancer Center Pathology Core, which performed embedding, sectioning and staining of prostate tissues, has been supported by National Institutes of Health grants P20 GM103639 and P30 CA225520. In addition, this work was partially funded by a postdoctoral fellowship from the Department of Defense Prostate Cancer Research Program (W81XWH-13-1-0083 to S.O.) and by a grant from the National Institutes of Health/ National Cancer Institute (R01 CA154745 to R.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the granting agencies.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The ETS transcription factor ETV1 is frequently overexpressed in aggressive prostate cancer, which is one underlying cause of this disease. Accordingly, transgenic mice that prostate-specifically overexpress ETV1 develop prostatic intraepithelial neoplasia. However, progression to the adenocarcinoma stage is stifled in these mice, suggesting that inhibitory pathways possibly preclude ETV1 from exerting its full oncogenic potential. Here we provide evidence that TGF-β/SMAD signaling represents such an inhibitory pathway. First, we discovered that ETV1 forms complexes with SMAD4. Second, SMAD2, SMAD3 and SMAD4 overexpression impaired ETV1’s ability to stimulate gene transcription. Third, TGF-β1 inhibited ETV1-induced invasion by benign RWPE-1 prostate cells. Fourth, increased expression of SMAD3 and SMAD4 was observable in prostates of ETV1 transgenic mice. Conversely, we found that ETV1 may enhance TGF-β signaling in PC3 prostate cancer cells, revealing a different facet of the ETV1/TGF-β interplay. Altogether, these data provide more insights into the regulation and action of ETV1 and additionally suggest that TGF-β/SMAD signaling exerts its tumor suppressive activity, at least in part, by curtailing the oncogenic potential of ETV1 in prostatic lesions.
AB - The ETS transcription factor ETV1 is frequently overexpressed in aggressive prostate cancer, which is one underlying cause of this disease. Accordingly, transgenic mice that prostate-specifically overexpress ETV1 develop prostatic intraepithelial neoplasia. However, progression to the adenocarcinoma stage is stifled in these mice, suggesting that inhibitory pathways possibly preclude ETV1 from exerting its full oncogenic potential. Here we provide evidence that TGF-β/SMAD signaling represents such an inhibitory pathway. First, we discovered that ETV1 forms complexes with SMAD4. Second, SMAD2, SMAD3 and SMAD4 overexpression impaired ETV1’s ability to stimulate gene transcription. Third, TGF-β1 inhibited ETV1-induced invasion by benign RWPE-1 prostate cells. Fourth, increased expression of SMAD3 and SMAD4 was observable in prostates of ETV1 transgenic mice. Conversely, we found that ETV1 may enhance TGF-β signaling in PC3 prostate cancer cells, revealing a different facet of the ETV1/TGF-β interplay. Altogether, these data provide more insights into the regulation and action of ETV1 and additionally suggest that TGF-β/SMAD signaling exerts its tumor suppressive activity, at least in part, by curtailing the oncogenic potential of ETV1 in prostatic lesions.
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U2 - 10.1038/s41598-019-44685-3
DO - 10.1038/s41598-019-44685-3
M3 - Article
C2 - 31160676
AN - SCOPUS:85066636843
SN - 2045-2322
VL - 9
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 8186
ER -