A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth
- University of Adelaide, Australia
- South Australian Health and Medical Research Institute, Australia
- University of Sydney, Australia
- Flinders University, Australia
- University of New South Wales, Australia
- Queen's University Belfast, United Kingdom
Abstract
Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity, as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively-collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by ACC1 and mTOR; and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1.Sequencing data have been deposited in GEO under accession code GSE152254
-
The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD)National Cancer Institute, TCGA-PRAD.
-
Androgen receptor programming in human tissue implicates HOXB13 in prostate pathogenesis [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE56288 (GSM1358397).
-
Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE56288 (GSM1328950).
-
Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer [ChIP-Seq]NCBI The Gene Expression Omnibus, GSE73994 (GSM1907200).
-
SREBF1 ChIP-seq on human MCF-7NCBI The Gene Expression Omnibus, GSE91561 (ENCFF911YFI).
-
SREBF1 ChIP-seq on human HepG2 treated with insulinNCBI The Gene Expression Omnibus, GSE31477 (GSM935627; ENCFF000XXR).
Article and author information
Author details
Funding
Cancer Australia (1138766)
- Margaret M Centenera
- Ian G Mills
- David J Lynn
- Lisa M Butler
Movember Foundation (MRTA3)
- Andrew J Hoy
- Margaret M Centenera
- Luke A Selth
- Lisa M Butler
Prostate Cancer Foundation of Australia (MRTA3)
- Andrew J Hoy
- Margaret M Centenera
- Luke A Selth
- Lisa M Butler
Cancer Council South Australia (Principal Cancer Research Fellowships)
- Luke A Selth
- Lisa M Butler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Prostate cancer tissue was obtained with informed written consent through the Australian Prostate Cancer BioResource from men undergoing radical prostatectomy at St Andrew's Hospital (Adelaide, Australia). Ethical approval for the use of human prostate tumours was obtained from the Ethics Committees of the University of Adelaide (Adelaide, Australia) and St Andrew's Hospital (Adelaide, Australia). All experiments were performed in accordance with the guidelines of the National Health and Medical Research Council (Australia).
Copyright
© 2021, Gillis 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
-
- 2,576
- views
-
- 349
- downloads
-
- 24
- 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)
A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth
eLife 10:e62592.
https://doi.org/10.7554/eLife.62592
Further reading
-
- Cancer Biology
- Genetics and Genomics
Interpretation of variants identified during genetic testing is a significant clinical challenge. In this study, we developed a high-throughput CDKN2A functional assay and characterized all possible human CDKN2A missense variants. We found that 17.7% of all missense variants were functionally deleterious. We also used our functional classifications to assess the performance of in silico models that predict the effect of variants, including recently reported models based on machine learning. Notably, we found that all in silico models performed similarly when compared to our functional classifications with accuracies of 39.5–85.4%. Furthermore, while we found that functionally deleterious variants were enriched within ankyrin repeats, we did not identify any residues where all missense variants were functionally deleterious. Our functional classifications are a resource to aid the interpretation of CDKN2A variants and have important implications for the application of variant interpretation guidelines, particularly the use of in silico models for clinical variant interpretation.
-
- Cancer Biology
- Developmental Biology
Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in Trp53Y217C/Y217C (Trp53YC/YC) cells, and Trp53YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53-/- cells. Furthermore, Trp53YC/YC male mice died earlier than Trp53-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53YC/YC thymic cells compared to Trp53-/- cells. Surprisingly, we recovered only one Trp53YC/YC female for 22 Trp53YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53YC/YC female embryos with exencephaly and the death of most Trp53YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53YC/YC weaned females in their progeny. Together, these data suggest that the p53Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.
