The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer

Shan Wang, Rahul K. Kollipara, Caroline G. Humphries, Shi Hong Ma, Ryan Hutchinson, Rui Li, Javed Siddiqui, Scott A. Tomlins, Ganesh V. Raj, Ralf Kittler

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Ets related gene (ERG) is a transcription factor that is overexpressed in 40% of prostate tumors due to a gene fusion between ERG and TMPRSS2. Because ERG functions as a driver of prostate carcinogenesis, understanding the mechanisms that influence its turnover may provide new molecular handles to target the protein. Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation. Here, we identify Tripartite motif-containing protein 25 (TRIM25) as the E3 ubiquitin ligase that ubiquitinates the protein prior to its degradation. TRIM25 binds full-length ERG, and it also binds the N-terminally truncated variants of ERG that are expressed in tumors with TMPRSS2-ERG fusions. We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. TRIM25 mRNA and protein expression was increased in ERG rearrangement-positive prostate cancer specimens, and we provide evidence that ERG upregulates TRIM25 expression. Thus, overexpression of ERG in prostate cancer may cause an increase in TRIM25 activity, which is mitigated by the expression of the deubiquitinase USP9X, which is required to stabilize ERG.

Original languageEnglish (US)
Pages (from-to)64921-64931
Number of pages11
JournalOncotarget
Volume7
Issue number40
DOIs
StatePublished - 2016

Fingerprint

Ligases
Ubiquitin
Prostatic Neoplasms
Genes
Gene Fusion
Prostate
Tripartite Motif Proteins
Ubiquitin-Protein Ligases
Gene Rearrangement
Ubiquitination
Neoplasms
Carcinogenesis
Proteins
Transcription Factors
Up-Regulation
Messenger RNA

Keywords

  • Oncogene
  • Prostate cancer
  • Transcription factor
  • Ubiquitination

ASJC Scopus subject areas

  • Oncology

Cite this

The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer. / Wang, Shan; Kollipara, Rahul K.; Humphries, Caroline G.; Ma, Shi Hong; Hutchinson, Ryan; Li, Rui; Siddiqui, Javed; Tomlins, Scott A.; Raj, Ganesh V.; Kittler, Ralf.

In: Oncotarget, Vol. 7, No. 40, 2016, p. 64921-64931.

Research output: Contribution to journalArticle

Wang, S, Kollipara, RK, Humphries, CG, Ma, SH, Hutchinson, R, Li, R, Siddiqui, J, Tomlins, SA, Raj, GV & Kittler, R 2016, 'The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer', Oncotarget, vol. 7, no. 40, pp. 64921-64931. https://doi.org/10.18632/oncotarget.11915
Wang, Shan ; Kollipara, Rahul K. ; Humphries, Caroline G. ; Ma, Shi Hong ; Hutchinson, Ryan ; Li, Rui ; Siddiqui, Javed ; Tomlins, Scott A. ; Raj, Ganesh V. ; Kittler, Ralf. / The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer. In: Oncotarget. 2016 ; Vol. 7, No. 40. pp. 64921-64931.
@article{ac4171c962244c24a960901ce62743cd,
title = "The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer",
abstract = "Ets related gene (ERG) is a transcription factor that is overexpressed in 40{\%} of prostate tumors due to a gene fusion between ERG and TMPRSS2. Because ERG functions as a driver of prostate carcinogenesis, understanding the mechanisms that influence its turnover may provide new molecular handles to target the protein. Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation. Here, we identify Tripartite motif-containing protein 25 (TRIM25) as the E3 ubiquitin ligase that ubiquitinates the protein prior to its degradation. TRIM25 binds full-length ERG, and it also binds the N-terminally truncated variants of ERG that are expressed in tumors with TMPRSS2-ERG fusions. We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. TRIM25 mRNA and protein expression was increased in ERG rearrangement-positive prostate cancer specimens, and we provide evidence that ERG upregulates TRIM25 expression. Thus, overexpression of ERG in prostate cancer may cause an increase in TRIM25 activity, which is mitigated by the expression of the deubiquitinase USP9X, which is required to stabilize ERG.",
keywords = "Oncogene, Prostate cancer, Transcription factor, Ubiquitination",
author = "Shan Wang and Kollipara, {Rahul K.} and Humphries, {Caroline G.} and Ma, {Shi Hong} and Ryan Hutchinson and Rui Li and Javed Siddiqui and Tomlins, {Scott A.} and Raj, {Ganesh V.} and Ralf Kittler",
year = "2016",
doi = "10.18632/oncotarget.11915",
language = "English (US)",
volume = "7",
pages = "64921--64931",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "40",

}

TY - JOUR

T1 - The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer

AU - Wang, Shan

AU - Kollipara, Rahul K.

AU - Humphries, Caroline G.

AU - Ma, Shi Hong

AU - Hutchinson, Ryan

AU - Li, Rui

AU - Siddiqui, Javed

AU - Tomlins, Scott A.

AU - Raj, Ganesh V.

AU - Kittler, Ralf

PY - 2016

Y1 - 2016

N2 - Ets related gene (ERG) is a transcription factor that is overexpressed in 40% of prostate tumors due to a gene fusion between ERG and TMPRSS2. Because ERG functions as a driver of prostate carcinogenesis, understanding the mechanisms that influence its turnover may provide new molecular handles to target the protein. Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation. Here, we identify Tripartite motif-containing protein 25 (TRIM25) as the E3 ubiquitin ligase that ubiquitinates the protein prior to its degradation. TRIM25 binds full-length ERG, and it also binds the N-terminally truncated variants of ERG that are expressed in tumors with TMPRSS2-ERG fusions. We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. TRIM25 mRNA and protein expression was increased in ERG rearrangement-positive prostate cancer specimens, and we provide evidence that ERG upregulates TRIM25 expression. Thus, overexpression of ERG in prostate cancer may cause an increase in TRIM25 activity, which is mitigated by the expression of the deubiquitinase USP9X, which is required to stabilize ERG.

AB - Ets related gene (ERG) is a transcription factor that is overexpressed in 40% of prostate tumors due to a gene fusion between ERG and TMPRSS2. Because ERG functions as a driver of prostate carcinogenesis, understanding the mechanisms that influence its turnover may provide new molecular handles to target the protein. Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation. Here, we identify Tripartite motif-containing protein 25 (TRIM25) as the E3 ubiquitin ligase that ubiquitinates the protein prior to its degradation. TRIM25 binds full-length ERG, and it also binds the N-terminally truncated variants of ERG that are expressed in tumors with TMPRSS2-ERG fusions. We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. TRIM25 mRNA and protein expression was increased in ERG rearrangement-positive prostate cancer specimens, and we provide evidence that ERG upregulates TRIM25 expression. Thus, overexpression of ERG in prostate cancer may cause an increase in TRIM25 activity, which is mitigated by the expression of the deubiquitinase USP9X, which is required to stabilize ERG.

KW - Oncogene

KW - Prostate cancer

KW - Transcription factor

KW - Ubiquitination

UR - http://www.scopus.com/inward/record.url?scp=84994121022&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994121022&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.11915

DO - 10.18632/oncotarget.11915

M3 - Article

C2 - 27626314

AN - SCOPUS:84994121022

VL - 7

SP - 64921

EP - 64931

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 40

ER -