Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome profiling links intrinsic stem cell and proneural properties of basal epithelial cells to human prostate tumorigenesis

ABSTRACT: The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here, we describe a whole-genome transcriptome analysis of human benign prostatic basal and luminal populations by using deep RNA sequencing. Combined with comprehensive molecular and biological characterizations, we show that the differential gene expression profiles account for their distinct functional phenotypes. Strikingly, in contrast to luminal cells, basal cells preferentially express gene categories associated with stem cells, neural and neuronal development and RNA processing. Consistent with their expression profiles, basal cells functionally exhibit intrinsic stem-like and proneural properties with enhanced ribosome RNA (rRNA) transcription activity. Of clinical relevance, the treatment failed castration-resistant and anaplastic prostate cancers molecularly resemble a basal-like phenotype. Therefore, we link the cell-type specific gene signatures to subtypes of prostate cancer development, and identify genes associated with patient clinical outcome. Human total RNA profiles of 3 pairs of benign prostatic basal and luminal populations freshly purified from prostate tissues of three prostate cancer patients by deep RNA-seq.

ORGANISM(S): Homo sapiens

SUBMITTER: Dingxiao Zhang

PROVIDER: E-GEOD-67070 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Tissue remodeling or regeneration is believed to initiate from organ-specific stem and/or progenitor cells. We report here the establishment of two spontaneously immortalized adult human benign prostate epithelial cell lines, NHPrE1 and BHPrE1. NHPrE1CD133(++)/CD44(++)/OCT4(++)/CK14(+++) was characterized as a putative progenitor cell, and BHPrE1CD133(+)/CD44(+)/OCT4(+)/CK14(++) as a putative intermediate cell. aCGH analysis demonstrated a largely intact diploid karyotype with DNA amplification of PTEN in NHPrE1 or Beta-Catenin in BHPrE1 cells, respectively. A tissue recombination-xenografting model was utilized to compare remodeling of human prostatic tissues in vivo by the NHPrE1 and BHPrE1 cell lines and their parental primary cells. A series of tissue recombinants, made by mixing different ratios of human prostatic epithelial cells and inductive rat urogenital sinus mesenchyme (UGM), were grafted to the renal capsule of SCID mice. Both cell lines were able to regenerate ductal/acinar structures in vivo containing basal and luminal epithelial populations confirmed by the expression of appropriate cytokeratin profiles. Androgen receptor (AR), prostate specific antigen (PSA), and 15-lipoxigenase-2 (15-LOX-2) expression were appropriately expressed in the regenerated epithelial structures. Regeneration of benign human prostatic ductal/acinar architecture could be achieved using as few as 10 NHPrE1 cells while 200,000 BHPrE1 cells were required to achieve prostatic structure. This suggests a greater proportion of progenitor cells in NHPrE1 facilitated regeneration of prostatic morphology and function. These cell lines provide important data on progenitor and intermediate cell phenotypes and represent significant new tools for the elucidation of molecular mechanisms of human prostatic regeneration, pathogenesis and carcinogenesis. Two channel CGH from Agilent platform was used to detect DNA amplification or deletion in genomic samples from NHPrE1 and BHPrE1 cell lines. A common pooled normal DNA refernce was used.

Project description:Recurrent mutations in histone modifying enzymes in multiple cancer types imply key roles in tumorigenesis. However, the functional relevance of these mutations remains unknown. Here we show that the JARID1B histone H3 lysine 4 demethylase is frequently amplified and overexpressed in luminal breast tumors and a somatic point mutation of JARID1B leads to the gain of luminal-specific gene expression programs. Downregulation of JARID1B in luminal breast cancer cells induces the expression of basal cell-specific genes and growth arrest, which is partially rescued by the inhibition of TGFBR thereby indicating a key role for TGFb signaling. Integrated genome-wide analysis of JARID1B chromatin binding, histone H3 lysine trimethyl (H3K4me3) and dimethyl (H3K4me2) patterns, and gene expression profiles in luminal and basal-like breast cancer cells suggest a key role for JARID1B in luminal cell-specific gene expression programs. A significant fraction of JARID1B binding-sites overlaps with CTCF in both luminal and basal-like breast cancer cells. CTCF also co-immunoprecipitates with JARID1B and it may influence its histone demethylase (HDM) activity as the H3K4me3/me2 ratio is lower at the CTCF-overlapping compared to JARID1B-unique sites. Additionally, a heterozygous JARID1B missense mutation (K1435R) in the HCC2157 basal-like breast cancer cell line is associated with unique JARID1B chromatin-binding and gene expression patterns implying gain of luminal features. In line with this, exogenous expression of this mutant in basal-like breast cancer cells leads to a gain of JARID1B binding at many luminal-specific genes. A PARADIGM score reflecting JARID1B activity in luminal breast cancer cells is associated with poor clinical outcome in patients with luminal breast tumors. Together, our data imply that JARID1B is a luminal lineage-driving oncogene and that its therapeutic targeting may represent a novel therapeutic strategy in treatment-resistant luminal breast tumors. RNA-Seq in breast cancer cell-lines transfected with JARID1B/CTCF/control siRNA. 50 cycles of sequencing on Illumina platform.

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Transcriptome profiling links intrinsic stem cell and proneural properties of basal epithelial cells to human prostate tumorigenesis

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