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TRIM24 is an oncogenic transcriptional activator in prostate cancer


Abstract

Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.

Abstract

Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Urological Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:13 June 2016
Deposited On:28 Jul 2016 13:54
Last Modified:19 Aug 2018 03:45
Publisher:Cell Press (Elsevier)
ISSN:1535-6108
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.ccell.2016.04.012
PubMed ID:27238081
Project Information:
  • : FunderSNSF
  • : Grant IDP300P3_151145
  • : Project TitleThe role of TRIM24 as a hormone-independent transcriptional co-activator of the androgen receptor in castration-resistant prostate cancer
  • : FunderSNSF
  • : Grant IDPP00P3_150645
  • : Project TitleGenetically-Induced Aberrant Chromatin States in Prostate Cancer - Biology and Therapy
  • : FunderSNSF
  • : Grant IDPBNE2--110237
  • : Project TitleEtude des cyanobactéries comme une nouvelle source d'inhibiteurs du protéasome

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