Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer

Anshu Rastogi; Shyh Han Tan; Ahmed A. Mohamed; Yongmei Chen; Ying Hu; Gyorgy Petrovics; Taduru Sreenath; Jacob Kagan; Sudhir Srivastava; David G. McLeod; Isabell A. Sesterhenn; Shiv Srivastava; Albert Dobi; Alagarsamy Srinivasan

Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer

Anshu Rastogi, Shyh Han Tan, Ahmed A. Mohamed, Yongmei Chen, Ying Hu, Gyorgy Petrovics, Taduru Sreenath, Jacob Kagan, Sudhir Srivastava, David G. McLeod, Isabell A. Sesterhenn, Shiv Srivastava, Albert Dobi^*, Alagarsamy Srinivasan

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

The fusion between ERG coding sequences and the TMPRSS2 promoter is the most prevalent in prostate cancer (CaP). The presence of two main types of TMPRSS2-ERG fusion transcripts in CaP specimens, Type I and Type II, prompted us to hypothesize that the cumulative actions of different ERG variants may impact CaP development/progression. Using TMPRSS2-ERG3 (Type I) and TMPRSS2-ERG8 (Type II) expression vectors, we determined that the TMPRSS2-ERG8 encoded protein is deficient in transcriptional regulation compared to TMPRSS2-ERG3. Co-transfection of vectors resulted in decreased transcriptional regulation compared to TMPRSS2-ERG3 alone, suggesting transdominance of ERG8. Expression of exogenous ERG8 protein resulted in a decrease in endogenous ERG3 protein levels in TMPRSS2-ERG positive VCaP cells, with a concomitant decrease in C-MYC. Further, we showed a physical association between ERG3 and ERG8 in live cells by the bimolecular fluorescence complementation assay, providing a basis for the observed effects. Inhibitory effects of TMPRSS2-ERG8 on TMPRSS2-ERG3 were also corroborated by gene expression data from human prostate cancers, which showed a positive correlation between C-MYC expression and TMPRSS2-ERG3/TMPRSS2-ERG8 ratio. We propose that an elevated TMPRSS2-ERG3/TMPRSS2-ERG8 ratio results in elevated C-MYC in CaP, providing a strong rationale for the biomarker and therapeutic utility of ERG splice variants, along with C-MYC.

Original language	English
Pages (from-to)	273-284
Number of pages	12
Journal	Genes and Cancer
Volume	5
Issue number	7-8
State	Published - 2014
Externally published	Yes

Keywords

C-MYC
Dominant negative
ERG
Prostate cancer
Splice variants

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@article{8b7c8bcdeef74935875d27fff4c7b836,

title = "Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer",

abstract = "The fusion between ERG coding sequences and the TMPRSS2 promoter is the most prevalent in prostate cancer (CaP). The presence of two main types of TMPRSS2-ERG fusion transcripts in CaP specimens, Type I and Type II, prompted us to hypothesize that the cumulative actions of different ERG variants may impact CaP development/progression. Using TMPRSS2-ERG3 (Type I) and TMPRSS2-ERG8 (Type II) expression vectors, we determined that the TMPRSS2-ERG8 encoded protein is deficient in transcriptional regulation compared to TMPRSS2-ERG3. Co-transfection of vectors resulted in decreased transcriptional regulation compared to TMPRSS2-ERG3 alone, suggesting transdominance of ERG8. Expression of exogenous ERG8 protein resulted in a decrease in endogenous ERG3 protein levels in TMPRSS2-ERG positive VCaP cells, with a concomitant decrease in C-MYC. Further, we showed a physical association between ERG3 and ERG8 in live cells by the bimolecular fluorescence complementation assay, providing a basis for the observed effects. Inhibitory effects of TMPRSS2-ERG8 on TMPRSS2-ERG3 were also corroborated by gene expression data from human prostate cancers, which showed a positive correlation between C-MYC expression and TMPRSS2-ERG3/TMPRSS2-ERG8 ratio. We propose that an elevated TMPRSS2-ERG3/TMPRSS2-ERG8 ratio results in elevated C-MYC in CaP, providing a strong rationale for the biomarker and therapeutic utility of ERG splice variants, along with C-MYC.",

keywords = "C-MYC, Dominant negative, ERG, Prostate cancer, Splice variants",

author = "Anshu Rastogi and Tan, {Shyh Han} and Mohamed, {Ahmed A.} and Yongmei Chen and Ying Hu and Gyorgy Petrovics and Taduru Sreenath and Jacob Kagan and Sudhir Srivastava and McLeod, {David G.} and Sesterhenn, {Isabell A.} and Shiv Srivastava and Albert Dobi and Alagarsamy Srinivasan",

year = "2014",

language = "English",

volume = "5",

pages = "273--284",

journal = "Genes and Cancer",

issn = "1947-6019",

number = "7-8",

}

TY - JOUR

T1 - Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer

AU - Rastogi, Anshu

AU - Tan, Shyh Han

AU - Mohamed, Ahmed A.

AU - Chen, Yongmei

AU - Hu, Ying

AU - Petrovics, Gyorgy

AU - Sreenath, Taduru

AU - Kagan, Jacob

AU - Srivastava, Sudhir

AU - McLeod, David G.

AU - Sesterhenn, Isabell A.

AU - Srivastava, Shiv

AU - Dobi, Albert

AU - Srinivasan, Alagarsamy

PY - 2014

Y1 - 2014

N2 - The fusion between ERG coding sequences and the TMPRSS2 promoter is the most prevalent in prostate cancer (CaP). The presence of two main types of TMPRSS2-ERG fusion transcripts in CaP specimens, Type I and Type II, prompted us to hypothesize that the cumulative actions of different ERG variants may impact CaP development/progression. Using TMPRSS2-ERG3 (Type I) and TMPRSS2-ERG8 (Type II) expression vectors, we determined that the TMPRSS2-ERG8 encoded protein is deficient in transcriptional regulation compared to TMPRSS2-ERG3. Co-transfection of vectors resulted in decreased transcriptional regulation compared to TMPRSS2-ERG3 alone, suggesting transdominance of ERG8. Expression of exogenous ERG8 protein resulted in a decrease in endogenous ERG3 protein levels in TMPRSS2-ERG positive VCaP cells, with a concomitant decrease in C-MYC. Further, we showed a physical association between ERG3 and ERG8 in live cells by the bimolecular fluorescence complementation assay, providing a basis for the observed effects. Inhibitory effects of TMPRSS2-ERG8 on TMPRSS2-ERG3 were also corroborated by gene expression data from human prostate cancers, which showed a positive correlation between C-MYC expression and TMPRSS2-ERG3/TMPRSS2-ERG8 ratio. We propose that an elevated TMPRSS2-ERG3/TMPRSS2-ERG8 ratio results in elevated C-MYC in CaP, providing a strong rationale for the biomarker and therapeutic utility of ERG splice variants, along with C-MYC.

AB - The fusion between ERG coding sequences and the TMPRSS2 promoter is the most prevalent in prostate cancer (CaP). The presence of two main types of TMPRSS2-ERG fusion transcripts in CaP specimens, Type I and Type II, prompted us to hypothesize that the cumulative actions of different ERG variants may impact CaP development/progression. Using TMPRSS2-ERG3 (Type I) and TMPRSS2-ERG8 (Type II) expression vectors, we determined that the TMPRSS2-ERG8 encoded protein is deficient in transcriptional regulation compared to TMPRSS2-ERG3. Co-transfection of vectors resulted in decreased transcriptional regulation compared to TMPRSS2-ERG3 alone, suggesting transdominance of ERG8. Expression of exogenous ERG8 protein resulted in a decrease in endogenous ERG3 protein levels in TMPRSS2-ERG positive VCaP cells, with a concomitant decrease in C-MYC. Further, we showed a physical association between ERG3 and ERG8 in live cells by the bimolecular fluorescence complementation assay, providing a basis for the observed effects. Inhibitory effects of TMPRSS2-ERG8 on TMPRSS2-ERG3 were also corroborated by gene expression data from human prostate cancers, which showed a positive correlation between C-MYC expression and TMPRSS2-ERG3/TMPRSS2-ERG8 ratio. We propose that an elevated TMPRSS2-ERG3/TMPRSS2-ERG8 ratio results in elevated C-MYC in CaP, providing a strong rationale for the biomarker and therapeutic utility of ERG splice variants, along with C-MYC.

KW - C-MYC

KW - Dominant negative

KW - ERG

KW - Prostate cancer

KW - Splice variants

UR - http://www.scopus.com/inward/record.url?scp=84945939780&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:84945939780

SN - 1947-6019

VL - 5

SP - 273

EP - 284

JO - Genes and Cancer

JF - Genes and Cancer

IS - 7-8

ER -

Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer

Abstract

Keywords

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