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REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer.

ABSTRACT: Castration-resistance prostate cancer (CRPC), also known as hormone-refractory prostate cancer (HRPC), requires immediate attention since it is not only resistant to androgen ablation, chemo- and radiotherapy, but also highly metastatic. Increasing evidence suggests that enrichment of neuroendocrine (NE) cells is associated with CRPC. Here, combined RNA-seq and ChIP-seq analysis reveals that REST is involved in epithelial-mesenchymal transition (EMT) and stemness acquisition in NE differentiated prostate cancer (PCa) cells via direct transcriptional repression of Twist1 and CD44. Specifically we show that short-term knockdown of REST induces NE differentiation of LNCaP cells. Long-term REST knockdown enhanced the expression of Twist1 and CD44, cell migration and sphere formation. Overexpression of REST in hormone-refractory CWR22Rv1 PCa cells significantly reduces Twist1 and CD44 expression, cell migration and sphere formation. Collectively, our study uncovers REST in regulating EMT and stemness properties of NE PCa cells and suggests that REST is a potential therapeutic target for CRPC.

SUBMITTER: Chang YT

PROVIDER: S-EPMC5335619 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer.

Chang Yi-Ting YT Lin Tzu-Ping TP Campbell Mel M Pan Chin-Chen CC Lee Shu-Hui SH Lee Hsin-Chen HC Yang Muh-Hwa MH Kung Hsing-Jien HJ Chang Pei-Ching PC

Scientific reports 20170303

Castration-resistance prostate cancer (CRPC), also known as hormone-refractory prostate cancer (HRPC), requires immediate attention since it is not only resistant to androgen ablation, chemo- and radiotherapy, but also highly metastatic. Increasing evidence suggests that enrichment of neuroendocrine (NE) cells is associated with CRPC. Here, combined RNA-seq and ChIP-seq analysis reveals that REST is involved in epithelial-mesenchymal transition (EMT) and stemness acquisition in NE differentiated ...[more]

PMID: 28256535

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Project description:BackgroundAccumulating evidence demonstrated that NANOG1, the key transcription factor for embryonic stem cells, is associated with human cancers. NANOGP8, one of the pseudogenes in NANOG gene family, contains an intact open reading frame and also said to be expressed in cancer tissues. Therefore, a systematic study is greatly needed to address the following questions: among NANOG1 and NANOGP8, which gene is the main contributor for NANOG expression in cancer cells and which one is the key regulator responsible for stemness, epithelial-mesenchymal transition (EMT), metastasis, chemoresistance and other malignant phenotypes. Here we try to explore these issues with gastric adenocarcinoma cell lines in vitro using variety of molecular and cellular techniques.MethodsSpecial primers were designed to distinguish PCR products from NANOG1 and NANOGP8. Sphere-forming cells were cultured with serum-free and selective medium. A stable cell line was established with infection of lentivirus containing NANOGP8. qPCR was performed to measure NANOGP8 expression and its association with stemness, EMT and CSC markers in adherent cells and sphere-forming cells. Western blot analysis was deployed to confirm results of the transcript analysis. Experiments of cell proliferation, migration, invasion, clonogenic assay, sphere cell growth assays, cell cycle analysis, β-catenin accumulation and translocation in nucleus, and drug resistance were conducted to measure the impact of NANOGP8 on malignant statuses of gastric cancer cells. Immunofluorescence staining was used to analyze cell subpopulations with different markers.ResultsNANOGP8 is mainly responsible for NANOG expression in sphere-forming (stem cell-like) cells derived from gastric cancer cell lines regardless their differentiation status. Ectopic expression of NANOGP8 significantly up-regulates stemness transcription factors, EMT inducers, and cancer stem cell markers (CSC) including Lgr5. NANOGP8 also promotes expression of the signature genes vimentin and N-caderin for mesenchymal cells and down-regulates the signature gene E-caderin for epithelial cells whereby confer the cells with mesenchymal cell phenotype. In NANOGP8 over-expressed adherent and sphere-forming cells, Lgr5+ cells are significantly increased. Ectopic expression of NANOGP8 endows gastric cells with enhanced proliferation, migration, invasion, sphere-forming and clonogenic capacity, and chemoresistance. NANOGP8 expression also enhances β-catenin accumulation in nucleus and strengthens Wnt signal transduction.ConclusionNANOGP8 is the main regulator of gastric cancer stem cells. It is closely associated with EMT, stemness, and CSC marker as well as Wnt signal pathway. NANOGP8 is correlated with cell proliferation, migration, invasion, clonogenic capacity, β-catenin accumulation in nucleus, and chemoresistance in gastric cancer. NANOGP8 is a promising molecular target for clinical intervention of gastric cancer.

Dataset Information

REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer.

Publications

REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer.

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