Yeast-based evolutionary modeling of androgen receptor mutations and natural selection
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Published:2022-12-02
Issue:12
Volume:18
Page:e1010518
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ISSN:1553-7404
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Container-title:PLOS Genetics
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language:en
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Short-container-title:PLoS Genet
Author:
Zhang Haoran,
Zhang Lu,
Chen Shaoyong,
Yao Mingdong,
Ma Zhenyi,
Yuan YingjinORCID
Abstract
Cancer progression is associated with the evolutionary accumulation of genetic mutations that are biologically significant. Mutations of the androgen receptor (AR) are associated with the development of prostate cancer (PCa) by responding to non-androgenic hormones, and the lack of annotations in their responsiveness to hormone ligands remains a daunting challenge. Here, we have used a yeast reporter system to quickly evaluate the responsiveness of all fifty clinical AR mutations to a variety of steroidal ligands including dihydrotestosterone (DHT), 17β-estradiol (E2), progesterone (PROG), and cyproterone acetate (CPA). Based on an AR-driven reporter that synthesizes histidine, a basic amino acid required for yeast survival and propagation, the yeast reporter system enabling clonal selection was further empowered by combining with a random DNA mutagenesis library to simulate the natural evolution of AR gene under the selective pressures of steroidal ligands. In a time-frame of 1–2 weeks, 19 AR mutants were identified, in which 11 AR mutants were validated for activation by tested steroidal compounds. The high efficiency of our artificial evolution strategy was further evidenced by a sequential selection that enabled the discovery of multipoint AR mutations and evolution directions under the pressure of steroidal ligands. In summary, our designer yeast is a portable reporter module that can be readily adapted to streamline high-throughput AR-compound screening, used as a PCa clinical reference, and combined with additional bioassay systems to further extend its potential.
Funder
National Natural Science Foundation of China
National Key R&D Program of China
Publisher
Public Library of Science (PLoS)
Subject
Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics
Reference72 articles.
1. The clonal evolution of tumor cell populations;P. Nowell;Science (1979),1976
2. Dynamics of cancer progression;F Michor;Nat Rev Cancer,2004
3. The causes and consequences of genetic heterogeneity in cancer evolution;RA Burrell;Nature,2013
4. Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies;ME Gore;British Journal of Cancer,2011
5. Distant metastasis occurs late during the genetic evolution of pancreatic cancer;S Yachida;Nature,2010
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