<i>PCAT-1</i>, a Long Noncoding RNA, Regulates BRCA2 and Controls Homologous Recombination in Cancer

Prensner, John R.; Chen, Wei; Iyer, Matthew K.; Cao, Qi; Ma, Teng; Han, Sumin; Sahu, Anirban; Malik, Rohit; Wilder-Romans, Kari; Navone, Nora M.; Logothetis, Christopher J.; Araujo, John C.; Pisters, Louis L.; Tewari, Ashutosh; Canman, Christine E.; Knudsen, Karen E.; Kitabayashi, Naoki; Rubin, Mark A.; Demichelis, Francesca; Lawrence, Theodore S.; Chinnaiyan, Arul M.; Feng, Felix Y.

doi:10.1158/0008-5472.can-13-3159

Cited by 229 publications

(183 citation statements)

References 30 publications

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“…WST-1 assays (Roche, Basel, Switzerland) were performed after 72 h and readings were recorded at 440 nm as previously described. 21,23,24 GraphPad Prism software (La Jolla, CA, USA) was used to generate non-linear regression curves and calculate IC50 values. Table 1 displays the overall demographics of each cohort.…”

Section: Drug Sensitivitymentioning

confidence: 99%

High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

Zhao

Jackson

Kothari

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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BACKGROUND: Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets. METHODS: The high-density Affymetrix GeneChip platform, encompassing 41 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (ageo65) versus older (age ⩾ 65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated agespecific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men. RESULTS: Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients. CONCLUSIONS: Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do not adequately represent genetic heterogeneity of PCa related to age, and future clinical trials would benefit from stratification based on age.

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Section: Drug Sensitivitymentioning

confidence: 99%

High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

Zhao

Jackson

Kothari

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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“…One can surmise, for instance, that as epithelial progenitor cells proliferate, the acquisition of successive mutations within the genome across daughter generations provides an opportunity for such cells to undergo a process such as EMT [12] . Interestingly, PCAT1 is inversely correlated with BRCA2 expression in LNCaP cells, while the knockdown of PCAT1 resulted in the upregulation of BRCA2, a crucial component of the DNA repair pathway [184,185] . Moreover, PCAT1 overexpression alters the formation of RAD51 and ɣ-H2aX foci after radiation-induced DNA damage, while naturally occurring polymorphisms within the genome, such as rs7463708, can promote an enhanced proliferative and migratory state within prostate cancer cell lines [186] .…”

Section: Prostate Cancer Associated Transcriptmentioning

confidence: 99%

The role of long noncoding RNAs in cancer metastasis

Parsons¹,

Tayoun²,

Benado³

et al. 2018

JCMT

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Signaling pathways are tightly controlled systems that regulate the appropriate timing of gene expression required for the differentiation of cells down a particular lineage essential for proper tissue development. Proliferation, apoptosis and metabolic pathways are just a few examples of the signaling pathways that require fine-tuning, so as to control the proper development of a particular tissue type or organ system. An estimated 70% of the genome is actively transcribed, only 2% of which codes for known protein-coding genes. Long noncoding RNAs (lncRNAs) in particular, are a large and diverse class of RNAs > 200 nucleotides in length, and not translated into protein. lncRNAs are essential transcriptional and post-transcriptional regulators that control the expression of genes in a spatial, temporal, and cell context-dependent manner. The aberrant expression of lncRNAs is therefore linked with a number of chronic diseases including cardiac dysfunction, diabetes, and cancer. In this review, we highlight the specific role lncRNAs have in promoting the metastatic cascade across a number of epithelial cancer models.

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“…PCAT1 functions to promote cancer cell proliferation through mediating the upregulation of c-Myc and the repression of breast cancer 2, early onset (BRCA2) (35,36). Overexpression of alpha-methylacyl-CoA racemase (AMACR) is associated with an increased risk of cancer in numerous ethnicities, which has been evaluated using meta-analyses of 22 cohort and case-series studies (37).…”

Section: Genetic Biomarkers For Risk Stratification Of Aggressive Cancermentioning

confidence: 99%

The context of prostate cancer genomics in personalized medicine

Liu

2017

Oncology Letters

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Abstract. Prostate cancer is one of the most common types of cancer in males. Heterogeneous genomic aberrations may lead to prostate cancer onset, progression and metastasis. This heterogeneity also contributes to the variety in cancer risk and outcomes, different drug responses and progression, observed between individual patients. Classical prognostic factors, including prostate-specific antigen, Gleason Score and clinical tumor staging, are not sufficient to portray the complexity of a clinically relevant cancer diagnosis, risk prognosis, treatment choice and therapy monitoring. There is a requirement for novel genetic biomarkers in order to understand the oncogenic heterogeneity in a patient-personalized clinical setting and to improve the efficacy of risk prognosis and treatment choice. A number of biomarkers and gene panels have been established from patient sample cohort studies. These previous studies have provided distinct information to the investigation of heterogeneous malignancy in prostate cancer, which aids in clinical decision-making. Biomarker-guided therapies may facilitate the effective selection of drugs during early treatment; therefore, are beneficial to the individual patient. A non-invasive approach allows for convenient and repeated sampling to screen for cancer and monitor treatment response without the requirement for invasive tissue biopsies. With the current availability of numerous advanced technologies, reliable detection of the minimal tumor residues present following treatment may become clinical practice and, therefore, inform further in the field of personalized medicine.

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PCAT-1, a Long Noncoding RNA, Regulates BRCA2 and Controls Homologous Recombination in Cancer

Cited by 229 publications

References 30 publications

High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

The role of long noncoding RNAs in cancer metastasis

The context of prostate cancer genomics in personalized medicine

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