GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance
- Memorial Sloan Kettering Cancer Center, United States
- Albert Einstein College of Medicine, United States
Abstract
Genomic amplification of the androgen receptor (AR) is an established mechanism of antiandrogen resistance in prostate cancer. Here we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1. We demonstrate 100-fold heterogeneity in AR output within human prostate cancer cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting EP300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo. Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.
Data availability
RNA-seq data has been deposited in GEO under accession code GSE120720. ChIP-seq data has been deposited in GEO under accession code GSE120680
-
GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistanceNCBI Gene Expression Omnibus, GSE120720.
-
GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistanceNCBI Gene Expression Omnibus, GSE120680.
-
Integrative clinical genomics of advanced prostate cancerNCBI dbGap, phs000915.v1.p1.
-
The Molecular Taxonomy of Primary Prostate CancercBioPortal for Cancer Genomics.
Article and author information
Author details
Funding
Howard Hughes Medical Institute
- Charles L Sawyers
National Institutes of Health (CA008748)
- Charles L Sawyers
National Institutes of Health (CA155169)
- Charles L Sawyers
U.S. Department of Defense (W81XWH-15-1-0540)
- Eugine Lee
Starr Cancer Consortium (I10-0062)
- Charles L Sawyers
Iris & Junming Le Foundation
- Eugine Lee
National Institutes of Health (CA193837)
- Charles L Sawyers
National Institutes of Health (CA224079)
- Charles L Sawyers
National Institutes of Health (CA092629)
- Charles L Sawyers
National Institutes of Health (CA160001)
- Charles L Sawyers
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were performed in compliance with the approved institutional animal care and use committee (IACUC) protocols (#06-07-012) of the Research Animal Resource Center of Memorial Sloan Kettering Cancer Center.
Copyright
© 2019, Lee et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,611
- views
-
- 399
- downloads
-
- 18
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance
eLife 8:e41913.
https://doi.org/10.7554/eLife.41913
Further reading
-
- Cancer Biology
- Genetics and Genomics
Uveal melanoma (UM) is a rare melanoma originating in the eye’s uvea, with 50% of patients experiencing metastasis predominantly in the liver. In contrast to cutaneous melanoma, there is only a limited effectiveness of combined immune checkpoint therapies, and half of patients with uveal melanoma metastases succumb to disease within 2 years. This study aimed to provide a path toward enhancing immunotherapy efficacy by identifying and functionally validating tumor-reactive T cells in liver metastases of patients with UM. We employed single-cell RNA-seq of biopsies and tumor-infiltrating lymphocytes (TILs) to identify potential tumor-reactive T cells. Patient-derived xenograft (PDX) models of UM metastases were created from patients, and tumor sphere cultures were generated from these models for co-culture with autologous or MART1-specific HLA-matched allogenic TILs. Activated T cells were subjected to TCR-seq, and the TCRs were matched to those found in single-cell sequencing data from biopsies, expanded TILs, and in livers or spleens of PDX models injected with TILs. Our findings revealed that tumor-reactive T cells resided not only among activated and exhausted subsets of T cells, but also in a subset of cytotoxic effector cells. In conclusion, combining single-cell sequencing and functional analysis provides valuable insights into which T cells in UM may be useful for cell therapy amplification and marker selection.
-
- Cancer Biology
In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 Associated RNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.
