A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier (SLC) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.
The authors declare that all data generated or analyzed in this study are included in the published article, its supplementary information and source files, or are publicly available. The CHARGE-seq and RNA-seq datasets generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under the ascension codes GSE196251 and GSE196252, respectively. The custom python script used in the analysis of our Charge-seq study is available on GitHub (https://github.com/carlsonkPhD/tRNA_Charge-Seq/). Gene expression data from prostate cancer patients (PRAD) in the TCGA database used for correlation analysis is publicly available.
GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasisNCBI Gene Expression Omnibus, GSE196251.
GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasisNCBI Gene Expression Omnibus, GSE196252.
- Ronald C Wek
- Tracy G Anthony
- Robero Pili
- Kirk A Staschke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at Indiana University School of Medicine (Protocol #21014) and comply with all regulations for ethical conduct of animal research. Human prostate core needle biopsy specimens were obtained from the Indiana University Comprehensive Cancer Center Tissue Procurement and Distribution Core and approval was granted by the Institutional Review Board (IRB #1796) at the Office of Research Administration at Indiana University.
- Nima Sharifi, Cleveland Clinic, United States
- Received: June 15, 2022
- Accepted: September 14, 2022
- Accepted Manuscript published: September 15, 2022 (version 1)
© 2022, Cordova 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.
How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate RNA and protein abundances of genes with SCNAs, we provide insights into the rules of gene regulation. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong RNA-level regulation. Notable exceptions are plasma membrane protein complex genes, which show a weak protein-level regulation and a stronger RNA-level regulation. Strikingly, we find a strong negative association between the degree of RNA-level and protein-level regulation across genes and cellular pathways. Moreover, genes participating in the same pathway show a similar degree of RNA- and protein-level regulation. Pathways including translation, splicing, RNA processing, and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger RNA-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve one predominant mechanism of gene regulation at the protein level or at the RNA level.
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