scholarly journals CRISPR Screen Contributes to Novel Target Discovery in Prostate Cancer

2021 ◽  
Vol 22 (23) ◽  
pp. 12777
Author(s):  
Takuya Tsujino ◽  
Kazumasa Komura ◽  
Teruo Inamoto ◽  
Haruhito Azuma
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Genetic Screen ◽  
Patient Treatment ◽  
Crispr Screen ◽  
The Common ◽  
Novel Target ◽  
Generation Sequencing ◽  
Cancer Diseases

Prostate cancer (PCa) is one of the common malignancies in male adults. Recent advances in omics technology, especially in next-generation sequencing, have increased the opportunity to identify genes that correlate with cancer diseases, including PCa. In addition, a genetic screen based on CRISPR/Cas9 technology has elucidated the mechanisms of cancer progression and drug resistance, which in turn has enabled the discovery of new targets as potential genes for new therapeutic targets. In the era of precision medicine, such knowledge is crucial for clinicians in their decision-making regarding patient treatment. In this review, we focus on how CRISPR screen for PCa performed to date has contributed to the identification of biologically critical and clinically relevant target genes.

scholarly journals Differential Gene Expression in Patients With Prostate Cancer and in Patients With Parkinson Disease: an Example of Inverse Comorbidity

2021 ◽  
Author(s):  
Pietro Pepe ◽  
Simona Vetrano ◽  
Rossella Cannarella ◽  
Aldo E Calogero ◽  
Giovanna Marchese ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Causes Of Death ◽  
Genetic Factors ◽  
Target Genes ◽  
Lewy Bodies ◽  
Control Group ◽  
Healthy Donors ◽  
Differential Gene ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Prostate cancer (PCa) is one of the leading causes of death in Western countries. Environmental and genetic factors play a pivotal role in PCa etiology. Timely identification of the genetic causes is useful for an early diagnosis. Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder; it is associated with the presence of Lewy bodies (LBs) and genetic factors are involved in its pathogenesis. Several studies have indicated that the expression of target genes in patients with PD is inversely related to cancer development; this phenomenon has been named “inverse comorbidity”. The present study was undertaken to evaluate whether a genetic dysregulation occurs in opposite directions in patients with PD or PCa. In the present study, next-generation sequencing (NGS) transcriptome analysis was used to assess whether a genetic dysregulation in opposite directions occurs in patients with PD or PCa. The genes SLC30A1, ADO, SRGAP2C, and TBC1D12 resulted up-regulated in patients with PD compared to healthy donors as controls and down-regulated in patients with PCa compared with the same control group. These results support the hypothesis of the presence of inverse comorbidity between PD and PCa.

scholarly journals Transcriptomics Signature from Next-Generation Sequencing Data Reveals New Transcriptomic Biomarkers Related to Prostate Cancer

2019 ◽  
Vol 18 ◽  
pp. 117693511983552 ◽  
Author(s):  
Abedalrhman Alkhateeb ◽  
Iman Rezaeian ◽  
Siva Singireddy ◽  
Dora Cavallo-Medved ◽  
Lisa A Porter ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Next Generation Sequencing ◽  
Cancer Progression ◽  
Machine Learning Techniques ◽  
Next Generation Sequencing Data ◽  
Prognostic Indicators ◽  
Next Generation ◽  
Sequencing Data ◽  
Cancer Data ◽  
Generation Sequencing

Prostate cancer is one of the most common types of cancer among Canadian men. Next-generation sequencing using RNA-Seq provides large amounts of data that may reveal novel and informative biomarkers. We introduce a method that uses machine learning techniques to identify transcripts that correlate with prostate cancer development and progression. We have isolated transcripts that have the potential to serve as prognostic indicators and may have tremendous value in guiding treatment decisions. Analysis of normal versus malignant prostate cancer data sets indicates differential expression of the genes HEATR5B, DDC, and GABPB1-AS1 as potential prostate cancer biomarkers. Our study also supports PTGFR, NREP, SCARNA22, DOCK9, FLVCR2, IK2F3, USP13, and CLASP1 as potential biomarkers to predict prostate cancer progression, especially between stage II and subsequent stages of the disease.

scholarly journals Differential modulation of the androgen receptor for prostate cancer therapy depends on the DNA response element

2020 ◽  
Vol 48 (9) ◽  
pp. 4741-4755
Author(s):  
Steven Kregel ◽  
Pia Bagamasbad ◽  
Shihan He ◽  
Elizabeth LaPensee ◽  
Yemi Raji ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Target Genes ◽  
Normal Growth ◽  
Differential Modulation ◽  
Expression Of Genes ◽  
Prostate Cancer Therapy ◽  
Specific Factors

Abstract Androgen receptor (AR) action is a hallmark of prostate cancer (PCa) with androgen deprivation being standard therapy. Yet, resistance arises and aberrant AR signaling promotes disease. We sought compounds that inhibited genes driving cancer but not normal growth and hypothesized that genes with consensus androgen response elements (cAREs) drive proliferation but genes with selective elements (sAREs) promote differentiation. In a high-throughput promoter-dependent drug screen, doxorubicin (dox) exhibited this ability, acting on DNA rather than AR. This dox effect was observed at low doses for multiple AR target genes in multiple PCa cell lines and also occurred in vivo. Transcriptomic analyses revealed that low dox downregulated cell cycle genes while high dox upregulated DNA damage response genes. In chromatin immunoprecipitation (ChIP) assays with low dox, AR binding to sARE-containing enhancers increased, whereas AR was lost from cAREs. Further, ChIP-seq analysis revealed a subset of genes for which AR binding in low dox increased at pre-existing sites that included sites for prostate-specific factors such as FOXA1. AR dependence on cofactors at sAREs may be the basis for differential modulation by dox that preserves expression of genes for survival but not cancer progression. Repurposing of dox may provide unique opportunities for PCa treatment.

Kallikreins are involved in an miRNA network that contributes to prostate cancer progression

2014 ◽  
Vol 395 (9) ◽  
pp. 991-1001 ◽  
Author(s):  
Sara Samaan ◽  
Zsuzsanna Lichner ◽  
Qiang Ding ◽  
Carol Saleh ◽  
Joseph Samuel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Integrated Circuit ◽  
Serine Proteases ◽  
Target Genes ◽  
Target Prediction ◽  
Preliminary Evidence ◽  
Differentially Expressed ◽  
Prostate Cancer Progression ◽  
Microsatellite Repeats

Abstract MicroRNAs (miRNAs) are short RNA nucleotides that negatively regulate their target genes. They are differentially expressed in prostate cancer. Kallikreins are genes that encode serine proteases and are dysregulated in cancer. We elucidated a miRNA-kallikrein network that can be involved in prostate cancer progression. Target prediction identified 23 miRNAs that are dysregulated between high and low risk biochemical failure and are predicted to target five kallikreins linked to prostate cancer; KLK2, KLK3, KLK4, KLK14 and KLK15. We also identified 14 miRNAs that are differentially expressed between Gleason grades and are predicted to target these kallikreins. This demonstrates that kallikreins are downstream effectors through which miRNAs influence tumor progression. We show, through in-silico and experimental analysis, that miR-378/422a and its gene targets PIK3CG, GRB2, AKT3, KLK4 and KLK14 form an integrated circuit in prostate cancer. Our analysis shows that a minisatellite sequence in the kallikrein locus consists of a number of microsatellite repeats that represent predicted miRNA response elements. A number of kallikrein and non-kallikrein prostate cancer-related genes share these microsatellite repeats. We validated some of these interactions in prostate cancer cell lines. Finally, we provide preliminary evidence on the presence of a miRNA-mediated cross-talk between kallikreins, including a kallikrein pseudogene.

scholarly journals A Splicing Variant of the Androgen Receptor Detected in a Metastatic Prostate Cancer Exhibits Exclusively Cytoplasmic Actions

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4334-4343 ◽  
Author(s):  
Monika Jagla ◽  
Marie Fève ◽  
Pascal Kessler ◽  
Gaëlle Lapouge ◽  
Eva Erdmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Dna Binding ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Splicing Variant ◽  
Activation Of Transcription

The androgen receptor (AR) is a ligand-activated transcription factor that displays genomic actions characterized by binding to androgen-response elements in the promoter of target genes as well as nongenomic actions that do not require nuclear translocation and DNA binding. In this study, we report exclusive cytoplasmic actions of a splicing variant of the AR detected in a metastatic prostate cancer. This AR variant, named AR23, results from an aberrant splicing of intron 2, wherein the last 69 nucleotides of the intronic sequence are retained, leading to the insertion of 23 amino acids between the two zinc fingers in the DNA-binding domain. We show that the nuclear entry of AR23 upon dihydrotestosterone (DHT) stimulation is impaired. Alternatively, DHT-activated AR23 forms cytoplasmic and perinuclear aggregates that partially colocalize with the endoplasmic reticulum and are devoid of genomic actions. However, in LNCaP cells, this cytoplasmic DHT-activated AR23 remains partially active as evidenced by the activation of transcription from androgen-responsive promoters, the stimulation of NF-κB transcriptional activity and by the decrease of AP-1 transcriptional activity. Our data reveal novel cytoplasmic actions for this splicing AR variant, suggesting a contribution in prostate cancer progression.

scholarly journals The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

2019 ◽  
Vol 218 (6) ◽  
pp. 1943-1957 ◽  
Author(s):  
Dawid G. Nowak ◽  
Ksenya Cohen Katsenelson ◽  
Kaitlin E. Watrud ◽  
Muhan Chen ◽  
Grinu Mathew ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Genetically Engineered ◽  
Phosphatase Inhibitors ◽  
Genetically Engineered Mouse Model ◽  
Key Driver ◽  
The Common ◽  
Chromosome 16Q ◽  
Mutant Cells

Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill PTEN mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.

The emerging role of noncoding RNA in prostate cancer progression and its implication on diagnosis and treatment

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Castration Resistant Prostate Cancer ◽  
Systematic Analysis ◽  
Castration Resistant ◽  
Insight Into ◽  
Generation Sequencing

Recent transcriptome studies using next-generation sequencing have detected aberrant changes in the expression of noncodingRNAs (ncRNAs) associated with cancer. For prostate cancer, the expression levels of ncRNAs including microRNAsand long noncoding RNAs are strongly associated with diagnosis, carcinogenesis and tumor growth. Moreover, androgenand its cognate receptor, androgen receptor (AR), regulate various signaling pathways for prostate tumor growth. In addition,progression to lethal castration-resistant prostate cancer (CRPC) is also owing to AR function. Systematic analysis ofAR-binding sites and their regulated transcripts revealed that many ncRNAs are widely regulated at the transcriptionallevel. Thus, recent studies provide new insight into the complicated molecular mechanism of prostate cancer progression.This review focused on the role of various ncRNAs in prostate cancer and the association between their expression andCRPC.

Altered corepressor SMRT expression and recruitment to target genes as a mechanism that change the response to androgens in prostate cancer progression

2012 ◽  
Vol 423 (3) ◽  
pp. 564-570 ◽  
Author(s):  
Alejandro S. Godoy ◽  
Paula C. Sotomayor ◽  
Marcelo Villagran ◽  
Rami Yacoub ◽  
Viviana P. Montecinos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Prostate Cancer Progression

scholarly journals MicroRNAs and Natural Compounds Mediated Regulation of TGF Signaling in Prostate Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zeeshan Javed ◽  
Khushbukhat Khan ◽  
Amna Rasheed ◽  
Haleema Sadia ◽  
Shahid Raza ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Therapeutic Option ◽  
Natural Compounds ◽  
Male Population ◽  
Cellular Processes ◽  
Low Cytotoxicity

Prostate cancer (PCa) is with rising incidence in male population globally. It is a complex anomaly orchestrated by a plethora of cellular processes. Transforming growth factor-beta (TGF-β) signaling is one of the key signaling pathways involved in the tumorigenesis of PCa. TGF-β signaling has a dual role in the PCa, making it difficult to find a suitable therapeutic option. MicroRNAs (miRNAs) mediated regulation of TGF-β signaling is responsible for the TGF-ß paradox. These are small molecules that modulate the expression of target genes and regulate cancer progression. Thus, miRNAs interaction with different signaling cascades is of great attention for devising new diagnostic and therapeutic options for PCa. Natural compounds have been extensively studied due to their high efficacy and low cytotoxicity. Here, we discuss the involvement of TGF-ß signaling in PCa with the interplay between miRNAs and TGF-β signaling and also review the role of natural compounds for the development of new therapeutics for PCa.

Oligometastatic prostate cancer patients stratification: A molecular signature identified by liquid biopsy.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS400-TPS400 ◽  
Author(s):  
Luca Triggiani ◽  
Lilia Bardoscia ◽  
Antonella Colosini ◽  
Simona Bernardi ◽  
Roberto Bresciani ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Peripheral Blood ◽  
Liquid Biopsy ◽  
Target Genes ◽  
Clonal Evolution ◽  
Initial Step ◽  
Molecular Signature ◽  
Rapid Progression ◽  
Oligometastatic Prostate Cancer

TPS400 Background: Oligometastatic prostate cancer (OPC) may represent the initial step of an unavoidable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time. In the last scenario, stereotactic body radiation therapy (SBRT) can be considered as a potentially curative treatment option for hormone-naïve OPC. We propose a prospective, explorative trail with the aim of identifying by liquid biopsy a molecular signature (genes or differential expression of miRNA), and related clonal evolution, underlying metastatic prostate cancer progression after a course of SBRT. Methods: Study population will be 30 adult, hormone-naïve OPC undergoing SBRT. Table 1 summarizes gene and miRNA panel for molecular analysis. For each patient, 15 ml of peripheral blood will be collected before and at the end of SBRT, every 3 months for the first year, then every 6 months until disease progression, when another blood sample will be collected in case of instrumental evidence of failure (using PET-Choline or CT-scan plus bone scintigraphy). 7.5 ml of peripheral blood will be centrifuged to separate sera and 7.5 ml of peripheral blood will be centrifuged to separate plasma from the other blood components, respectively. Sera and plasma will be stored at -20°C and centralized to CREA Laboratory at our Institution, then immediately processed for cell free DNA (cfDNA) and miRNA extraction for NGS of target genes (by Illumina platforms MiSeq and MiniSeq) and dPCR analysis. Study duration will be 36 months. This protocol has been written and will be conducted in agreement with either the Declaration of Helsinki and subsequent amendments and ICH Harmonized Tripartite Guideline for Good Clinical Practice, and has received approval of local Ethics Committee. Panel for analysis. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document