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CRISPR/Cas9 targeting of the androgen receptor suppresses the growth of LNCaP human prostate cancer cells.

ABSTRACT: Androgens have been recognized to be primary causative agents of prostate cancer. Following binding to the androgen receptor (AR), androgens serve important roles in the carcinogenesis of prostate cancers. ARs serve an important role during all stages of prostate cancer, and inhibiting their function may help to slow prostate cancer growth. In the present study, the AR gene was targeted in androgen?positive prostate cancer cells using the clustered regularly interspaced short palindromic repeats?associated protein (CRISPR/Cas) system. A total of three different single?guide RNAs (sgRNAs) were designed according to the three different target sites in the AR gene. The optimal sgRNA with a specific target effect was effectively screened to cleave the AR gene in androgen?positive prostate cancer cell lines, and to suppress the growth of androgen?sensitive prostate cancer in vitro. The AR?sgRNA?guided CRISPR/Cas system was able to disrupt the AR at specific sites and inhibit the growth of androgen?sensitive prostate cancer cells; further studies demonstrated that the decreased cell proliferation was due to cellular apoptosis. The results of the present study suggested that the CRISPR/Cas system may be a useful therapeutic strategy for the treatment of prostate cancer.

SUBMITTER: Wei C

PROVIDER: S-EPMC5783506 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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CRISPR/Cas9 targeting of the androgen receptor suppresses the growth of LNCaP human prostate cancer cells.

Wei Chaogang C Wang Fengjiao F Liu Wei W Zhao Wenlu W Yang Yi Y Li Kai K Xiao Li L Shen Junkang J

Molecular medicine reports 20171212 2

Androgens have been recognized to be primary causative agents of prostate cancer. Following binding to the androgen receptor (AR), androgens serve important roles in the carcinogenesis of prostate cancers. ARs serve an important role during all stages of prostate cancer, and inhibiting their function may help to slow prostate cancer growth. In the present study, the AR gene was targeted in androgen‑positive prostate cancer cells using the clustered regularly interspaced short palindromic repeats ...[more]

PMID: 29257308

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Project description:BackgroundGPRC6A is implicated in the pathogenesis of prostate cancer, but its role remains uncertain because of a purported tolerant gene variant created by substitution of a K..Y polymorphism in the 3rd intracellular loop (IL) that evolved in the majority of humans and replaces the ancestral RKLP present in 40% of humans of African descent and all other species.MethodsWe determined whether the K..Y polymorphism is present in human-derived prostate cancer cell lines by sequencing the region of the 3rd IL and assessed the cellular localization of a "humanized" mouse GPRC6A containing the K..Y sequence by immunofluorescence. We assessed functions of GPRC6A in PC-3 cells expressing endogenous GPRC6A and in GPRC6A-deficient PC-3 cells created using CRISPR/Cas9 technology. The effect of GPRC6A on basal and ligand stimulated cell proliferation and migration was evaluated in vitro in wild-type and PC-3-deficient cell lines. The effect of editing GPRC6A on prostate cancer growth and progression in vivo was assessed in a Xenograft mouse model implanted with wild-type and PC-3 deficient cells and treated with the GPRC6A ligand osteocalcin.ResultsWe found that all of the human prostate cancer cell lines tested endogenously express the "K..Y" polymorphism in the 3rd IL. Comparison of mouse wild-type GPRC6A with a "humanized" mouse GPRC6A construct created by replacing the "RKLP" with the "K..Y" sequence, found that both receptors were predominantly expressed on the cell surface. The transfected "humanized" GPRC6A receptor, however, preferentially activated mTOR compared to ERK signaling in HEK-293 cells. In contrast, in PC-3 cells expressing the endogenous GPRC6A with the "K..Y" polymorphism, the ligand osteocalcin stimulated ERK, AKT and mTOR phosphorylation, promoted cell proliferation and migration, and upregulated genes regulating testosterone biosynthesis. Targeting GPRC6A in PC-3 cells by CRISPR/Cas9 significantly blocked these responses in vitro. In addition, GPRC6A deficient PC-3 xenografts exhibited significantly less growth and were resistant to osteocalcin-induced prostate cancer progression compared to control PC-3 cells expressing GPRC6A.ConclusionsHuman GPRC6A is a functional osteocalcin and testosterone sensing receptor that promotes prostate cancer progression. GPRC6A may contribute to racial disparities in prostate cancer, and is a potential therapeutic target to develop antagonists to treat prostate cancer.

Dataset Information

CRISPR/Cas9 targeting of the androgen receptor suppresses the growth of LNCaP human prostate cancer cells.

Publications

CRISPR/Cas9 targeting of the androgen receptor suppresses the growth of LNCaP human prostate cancer cells.

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