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Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N 7 -methylguanosine (m 7 G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m 7 G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m 7 G tRNA methylation in cancer cell translation control and tumour biology.

Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.

Background Metastatic hormone-naïve prostate cancer (mHNPC) is an infrequent form of this tumor type that is characterized by metastasis at the time of diagnosis and accounts for up to 50% of prostate cancer-related deaths. Despite the extensive characterization of localized and metastatic castration-resistant prostate cancer, the molecular characteristics of mHNPC remain largely unexplored. Results Here, we provide the first extensive transcriptomics characterization of primary tumor specimens from patients with mHNPC. We generate discovery and validation bulk and single-cell RNA-seq datasets and perform integrative computational analysis in combination with experimental studies. Our results provide unprecedented evidence of the distinctive transcriptional profile of mHNPC and identify stroma remodeling as a predominant feature of these tumors. Importantly, we discover a central role for the SRY-box transcription factor 11 (SOX11) in triggering a heterotypic communication that is associated with the acquisition of metastatic properties. Conclusions Our study will constitute an invaluable resource for a profound understanding of mHNPC that can influence patient management.

Prostate cancer is a prevalent tumor type that, despite being highly curable, progresses to metastatic disease in a fraction of patients, thus accounting for more than 350 000 annual deaths worldwide. In turn, uncovering the molecular insights of metastatic disease is instrumental in improving the survival rate of prostate cancer patients. By means of gene expression meta‐analysis in multiple prostate cancer patient cohorts, we identified a set of genes that are differentially expressed in aggressive prostate cancer. Transcription factor 19 (TCF19) stood out as an unprecedented epithelial gene upregulated in metastatic disease, with prognostic potential and negatively associated with the activity of the androgen receptor. By combining computational and empirical approaches, our data revealed that TCF19 is required for full metastatic capacity, and its depletion influences core cancer‐related processes, such as tumor growth and vascular permeability, supporting the role of this gene in the dissemination of prostate tumor cells. Gene expression meta‐analysis in multiple prostate cancer patient cohorts identifies Transcription factor 19 (TCF19) as an aggressiveness‐sustaining gene with prognostic potential. TCF19 is a gene repressed by androgen signaling that sustains core cancer‐related processes such as vascular permeability or tumor growth and metastasis.

Prostate cancer exhibits high prevalence and accounts for a high number of cancer-related deaths. The discovery and characterization of molecular determinants of aggressive prostate cancer represents an active area of research. The Immediate Early Response (IER) family of genes, which regulate Protein Phosphatase 2A (PP2A) activity, has emerged among the factors that influence cancer biology. Here, we show that the less studied member of this family, Immediate Early Response 5 like (IER5L), is upregulated in aggressive prostate cancer. Interestingly, the upregulation of IER5L expression exhibits a robust association with metastatic disease in prostate and is recapitulated in other cancer types. In line with this observation, IER5L silencing reduces foci formation, migration and invasion ability in a variety of human and murine prostate cancer cell lines. In vivo, using zebrafish and immunocompromised mouse models, we demonstrate that IER5L -silencing reduces prostate cancer tumor growth, dissemination, and metastasis. Mechanistically, we characterize the transcriptomic and proteomic landscapes of IER5L -silenced cells. This approach allowed us to identify DNA replication and monomeric G protein regulators as downstream programs of IER5L through a pathway that is consistent with the regulation of PP2A. In sum, we report the alteration of IER5L in prostate cancer and beyond and provide biological and molecular evidence of its contribution to tumor aggressiveness.

Prostate cancer is the fifth cause of death by cancer worldwide, second in incidence in the male population. The definition of the molecular basis of its development and the oncogenic signals driving lethality continue to be important objectives in prostate cancer research. Prior work from others and us has demonstrated that loss of PGC1α expression results in a metabolic, signaling and transcriptional reprogramming that supports the development of metastatic disease. However, we do not fully understand the spectrum of tumor suppressive effects regulated by this co-regulator. Here we show that PGC1α governs non-cell autonomous paracrine tumor suppression in prostate cancer. A systematic analysis of the transcriptional landscapes associated to PGC1α loss of expression revealed that PGC1α alters the expression of genes encoding for secreted proteins. Cell secretome studies corroborated that PGC1α-dependent ERRα regulation in prostate cancer cells suppresses the growth of tumor cells exposed to their conditioned media, independently of androgen receptor status. The integration of in vitro and in vivo secretomics data and genetic perturbation assays revealed spermidine synthase as a transcriptional target of PGC1α and mediator of the paracrine metabolic growth suppressive effect. Moreover, the activity of the regulatory axis PGC1α-ERRα-SRM was reflected in patients and had prognostic value. Altogether, this work provides unprecedented evidence of the non-cell autonomous suppressive role of PGC1α, which broadens the view of this co-regulator as a multifactorial tumor suppressor in prostate cancer.

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.

Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts. A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data. Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11-1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14-1.53)]. Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.

Background Q fever, a worldwide zoonotic disease caused by Coxiella burnetii , is endemic in northern Spain where it has been reported as responsible for large series of human pneumonia cases and domestic ruminants' reproductive disorders. To investigate pathogen exposure among domestic ruminants in semi-extensive grazing systems in northern Spain, a serosurvey was carried out in 1,379 sheep (42 flocks), 626 beef cattle (46 herds) and 115 goats (11 herds). Serum antibodies were analysed by ELISA and positive samples were retested by Complement Fixation test (CFT) to detect recent infections. Results ELISA anti- C. burnetii antibody prevalence was slightly higher in sheep (11.8 ± 2.0%) than in goats (8.7 ± 5.9%) and beef cattle (6.7 ± 2.0%). Herd prevalence was 74% for ovine, 45% for goat and 43% for bovine. Twenty-one percent of sheep flocks, 27% of goat and 14% of cattle herds had a C. burnetii seroprevalence ≥ 20%. Only 15 out of 214 ELISA-positive animals reacted positive by CFT. Age-associated seroprevalence differed between ruminant species with a general increasing pattern with age. No evidence of correlation between abortion history and seroprevalence rates was observed despite the known abortifacient nature of C. burnetii in domestic ruminants. Conclusions Results reported herein showed that sheep had the highest contact rate with C. burnetii in the region but also that cattle and goats should not be neglected as part of the domestic cycle of C. burnetii . This work reports basic epidemiologic patterns of C. burnetii in semi-extensive grazed domestic ruminants which, together with the relevant role of C. burnetii as a zoonotic and abortifacient agent, makes these results to concern both Public and Animal Health Authorities.