Emerging Roles of the Sirtuin Family

Studies using Saccharomyces cerevisiae revealed the existence of a unique family of proteins named Sirtuins. Sirtuins are highly conserved all the way from bacteria to humans. These proteins play important roles inside the cell, as nicotinamide adenine dinucleotide-dependent protein deacetylases. Sirtuins are major regulators of multiple cellular functions; they can modify the epigenetic landscape and are able to alter the proteome of the cell. Several studies have analyzed the role of sirtuins as a link between caloric restriction and aging. However, recent discoveries demonstrate new roles for these proteins. Sirtuins have also caught the attention of the biotechnology industry, and small molecule activators and inhibitors have been developed. The following review describes key aspects of sirtuin biology, presents the current situation of sirtuins in the biotechnology industry, and analyzes the emerging roles of sirtuins in cell metabolism, chromatin regulation, and cancer

Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer

ADN tumoral circulant; Medicina de precisió; Càncer de pròstataADN tumoral circulante; Medicina de precisión; Cáncer de próstataCirculating tumor DNA; Precision medicine; Prostate cancerContext Genomic stratification can impact prostate cancer (PC) care through diagnostic, prognostic, and predictive biomarkers that aid in clinical decision-making. The temporal and spatial genomic heterogeneity of PC together with the challenges of acquiring metastatic tissue biopsies hinder implementation of tissue-based molecular profiling in routine clinical practice. Blood-based liquid biopsies are an attractive, minimally invasive alternative. Objective To review the clinical value of blood-based liquid biopsy assays in PC and identify potential applications to accelerate the development of precision medicine. Evidence acquisition A systematic review of PubMed/MEDLINE was performed to identify relevant literature on blood-based circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles (EVs) in PC. Evidence synthesis Liquid biopsy has emerged as a practical tool to profile tumor dynamics over time, elucidating features that evolve (genome, epigenome, transcriptome, and proteome) with tumor progression. Liquid biopsy tests encompass analysis of DNA, RNA, and proteins that can be detected in CTCs, ctDNA, or EVs. Blood-based liquid biopsies have demonstrated promise in the context of localized tumors (diagnostic signatures, risk stratification, and disease monitoring) and advanced disease (response/resistance biomarkers and prognostic markers). Conclusions Liquid biopsies have value as a source of prognostic, predictive, and response biomarkers in PC. Most clinical applications have been developed in the advanced metastatic setting, where CTC and ctDNA yields are significantly higher. However, standardization of assays and analytical/clinical validation is necessary prior to clinical implementation

Somatic Copy-Number Alterations across Human Cancers from LncRNA Perspective

The genome of a tumor cell presents thousands of genomic alterations including base-substitutions and somatic copy number alterations (SCNAs). SCNAs comprise amplifications and deletions of big chromosomal regions usually containing hundreds of genes. Some of these regions harbor well-studied cancer drivers; however many others do not contain a known driver. The analysis of SCNA focusing on the non-coding genome helped us pinpoint a list of copy number altered long noncoding RNAs (lncRNAs). In order to validate our findings we experimentally characterized functionally and mechanistically a lncRNA amplified in lung cancer which we named LUAD-amp-1. LUAD-amp-1 acts as an oncogenic lncRNA, and its expression is induced by the transcription factor NF-B upon TNF treatment. Moreover, LUAD-amp-1 is implicated in the inhibition of a set of NF-B regulated genes including TNF itself. LUAD-amp-1 molecular mechanism relies on its association with SART3, altering its localization and modulating the nuclear translocation of its associated protein USP4

Somatic Copy-Number Alterations across Human Cancers from LncRNA Perspective

The genome of a tumor cell presents thousands of genomic alterations including base-substitutions and somatic copy number alterations (SCNAs). SCNAs comprise amplifications and deletions of big chromosomal regions usually containing hundreds of genes. Some of these regions harbor well-studied cancer drivers; however many others do not contain a known driver. The analysis of SCNA focusing on the non-coding genome helped us pinpoint a list of copy number altered long noncoding RNAs (lncRNAs). In order to validate our findings we experimentally characterized functionally and mechanistically a lncRNA amplified in lung cancer which we named LUAD-amp-1. LUAD-amp-1 acts as an oncogenic lncRNA, and its expression is induced by the transcription factor NF-B upon TNF treatment. Moreover, LUAD-amp-1 is implicated in the inhibition of a set of NF-B regulated genes including TNF itself. LUAD-amp-1 molecular mechanism relies on its association with SART3, altering its localization and modulating the nuclear translocation of its associated protein USP4

Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors

Inhibició de l’ATR; Resposta de danys a l’ADN; Càncer de pròstataInhibición de ATR; Respuesta al daño del ADN; Cancer de prostataATR inhibition; DNA damage response; Prostate cancerBackground Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond. Objective To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset. Design, setting, and participants We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model. Outcome measurements and statistical analysis ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models. Results and limitations Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models. Conclusions ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition.We gratefully acknowledge research funding for this work from Cancer Research UK, Prostate Cancer UK, the Movember Foundation through the London Movember Centre of Excellence ( CEO13_2-002 ), the Prostate Cancer Foundation (including Young Investigator Awards to Joaquin Mateo, Pasquale Rescigno, and Adam Sharp), Stand Up To Cancer, and the UK Department of Health through an Experimental Cancer Medicine Centre grant. Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator; research at the Royal Marsden Hospital is supported by a Biomedical Research Centre grant. Part of this work was also funded by a Deparment of Defense CDMRP Impact Award (W81XWH-18-1-0756) to Joaquin Mateo and by Instituto de Salud Carlos III through Grant FI19/00280 to Sara Arce-Gallego, Grant CP19/00170 to Nicolás Herranz, and Grant PI18/01384 to Joaquin Mateo. The authors affiliated to VHIO acknowledge the “la Caixa” Foundation ( ID 100010434 ) for funding under agreement LCF/PR/PR17/51120011 and funding from Fundacion FERO and Moventia . This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 837900 . The funding organisations had no role in the design, conduction or data analysis of this project, neither in the manuscript preparation

The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element

Background: It is now obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long non-coding RNAs (lncRNAs). Many lncRNAs show aberrant expression in cancer, and some of them have been linked to cell transformation. However, the underlying mechanisms remain poorly understood and it is unknown how the sequences of lncRNA dictate their function. Results: Here we characterize the function of the p53-regulated human lncRNA LINC-PINT in cancer. We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells. A cross-species analysis identifies a highly conserved sequence element in LINC-PINT that is essential for its function. This sequence mediates a specific interaction with PRC2, necessary for the LINC-PINT-dependent repression of a pro-invasion signature of genes regulated by the transcription factor EGR1. Conclusions: Our findings support a conserved functional co-dependence between LINC-PINT and PRC2 and lead us to propose a new mechanism where the lncRNA regulates the availability of free PRC2 at the proximity of co-regulated genomic loci