Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
- University of Adelaide, Australia
- KU Leuven, Belgium
- Olivia Newton-John Cancer Research Institute, Australia
- South Australian Health and Medical Research Institute, Australia
- University of Sydney, Australia
- University of New South Wales, Australia
- Chris O'Brien Lifehouse, Australia
Abstract
Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
-
Age-Related Gene Expression Changes in Prostate Cancer PatientsNCBI The Gene Expression Omnibus, GSE89194.
-
The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD)National Cancer Institute, TCGA-PRAD.
-
Integrative Molecular Concepts Modeling of Prostate Cancer ProgressionNCBI The Gene Expression Omnibus, GSE6099.
-
The Mutational Landscape of Lethal Castrate Resistant Prostate CancerNCBI The Gene Expression Omnibus, GSE35988.
-
Integrative genomic profiling of human prostate cancerNCBI The Gene Expression Omnibus, GSE21032.
-
Molecular Sampling of Prostate Cancer: a dilemma for predicting disease progressionNCBI The Gene Expression Omnibus, GSE16560.
-
A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growthNCBI The Gene Expression Omnibus, GSE7868.
-
Identification of an SRF- and androgen-dependent gene signature in prostate cancerNCBI The Gene Expression Omnibus, GSE22606.
-
Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate CancerNCBI The Gene Expression Omnibus, GSE55064.
-
Genome-wide analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cellsNCBI The Gene Expression Omnibus, GSE69249.
-
Expression profiling of the mouse prostate after castration and hormone replacementNCBI The Gene Expression Omnibus, GSE5901.
-
Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor BlockadeNCBI The Gene Expression Omnibus, GSE52169.
-
Androgen receptor programming in human tissue implicates HOXB13 in prostate pathogenesis [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE56288.
Article and author information
Author details
Funding
National Health and Medical Research Council (Early Career Fellowship,1138648)
- Zeyad D Nassar
KU Leuven (Project Grants C16/15/073 and C32/17/052)
- Johannes V Swinnen
Australian Research Council (Future Fellowship,FT130101004)
- Lisa M Butler
Cancer Council South Australia (Beat Cancer Fellowship,PRF1117)
- Lisa M Butler
Movember Foundation (Revolutionary Team Award,MRTA3)
- Lisa M Butler
National Health and Medical Research Council (Project Grant,1121057)
- Luke A Selth
National Health and Medical Research Council (Project Grant,1100626)
- Anthony S Don
National Health and Medical Research Council (Fellowship,1084178)
- Andrew M Scott
Prostate Cancer Foundation of Australia (Young Investigator Award,YI 1417)
- Zeyad D Nassar
Cure Cancer Australia Foundation (Project Grant,1164798)
- Zeyad D Nassar
EMBL Australia (Group Leader Award)
- David J Lynn
University of Sydney (Robinson Fellowship)
- Andrew J Hoy
Fonds Wetenschappelijk Onderzoek (Project Grants G.0841.15 and G.0C22.19N)
- Johannes V Swinnen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal studies were approved by the Austin Health Animal Ethics Committee (approval number A2015/05311), Heidelberg, Australia, and the University of Adelaide Animal Ethics Committee (approval number M-2019-037), and were carried out in accordance with the recommendations of the National Health and Medical Research Council of Australia.
Human subjects: Fresh and archival prostate tissue specimens were collected from men undergoing robotic radical prostatectomy at St. Andrew's Hospital (Adelaide, South Australia) with written informed consent through the Australian Prostate Cancer BioResource. Ethical Approval was provided by the Human Research Ethics Committees of the University of Adelaide (H-2012-016) and St Andrew's Hospital.
Copyright
© 2020, Nassar 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
-
- 4,767
- views
-
- 723
- downloads
-
- 125
- 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)
Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
eLife 9:e54166.
https://doi.org/10.7554/eLife.54166
Further reading
-
- Cancer Biology
- Immunology and Inflammation
The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.
-
- Cancer Biology
- Computational and Systems Biology
Effects from aging in single cells are heterogenous, whereas at the organ- and tissue-levels aging phenotypes tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages: luminal epithelial and myoepithelial cells. Mammary luminal epithelia exhibit substantial stereotypical changes with age that merit attention because these cells are the putative cells-of-origin for breast cancers. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increase susceptibility to cancer initiation. We generated and analyzed transcriptomes from primary luminal epithelial and myoepithelial cells from younger <30 (y)ears old and older >55 y women. In addition to age-dependent directional changes in gene expression, we observed increased transcriptional variance with age that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and involved altered regulation of chromatin and genome organizers such as SATB1. Epithelial expression variance of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal that could be detected in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was highly predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype both endows cells with the ability to become cancer-cells-of-origin and represents a biosensor that presages cancer susceptibility.
