Explore the vast range of titles available.

Among the extensive genomic alterations in prostate cancer, phosphatase and tensin homolog (PTEN) deletion stands out as one of the most consistently observed events. PTEN loss in prostate tumors is primarily associated with cancer‐cell proliferation and survival through the activation of the phosphoinositide 3‐kinase (PI3K)—protein kinase B (AKT)—mechanistic target of rapamycin (mTOR) (PI3K–AKT–mTOR) signaling pathway. However, the use of PTEN as a robust biomarker in clinical practice is hampered by its complex epigenetic, transcriptional and post‐translational regulation. In situ protein assessment by immunohistochemistry (IHC) captures PTEN protein status, but it does not report on associated tumor microenvironment remodeling. Here, we undertook an approach that combined PTEN immunoreactivity analysis with high‐throughput transcriptional analysis to gain insights into the downstream functional effects of PTEN protein loss in primary tumors. Our extensive bioinformatic analyses highlighted stromal remodeling as a prominent cancer cell‐extrinsic process associated with PTEN loss. By extending our transcriptomic computational strategy to Pten loss‐driven murine prostate cancer, we validated the causal role of Pten in the stromal reaction observed in clinical specimens. Mechanistically, we provide experimental evidence for the activation of a paracrine program that encompasses enhanced transforming growth factor beta (TGF‐β) signaling and that is compatible with the secretome of PTEN‐deficient senescent cancer cells. Finally, our findings enable the sub‐stratification of tumors with PTEN loss based on their senescence‐associated stroma remodeling program to distinguish indolent from aggressive cases. Our study provides relevant biological context to the cellular and molecular alterations unleashed upon PTEN protein loss in prostate cancer. Combining PTEN protein assessment and transcriptomic profiling of prostate tumors, we uncovered a network enriched in senescence and extracellular matrix (ECM) programs associated with PTEN loss and conserved in a mouse model. We show that PTEN‐deficient cells trigger paracrine remodeling of the surrounding stroma and this information could help stratify PTEN‐negative tumors according to clinical aggressiveness.

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.

Oxygen availability is frequently compromised in solid tumours, making intratumoural hypoxia a common feature of cancer. In prostate cancer (PCa), hypoxia is strongly associated with aggressive disease and poor prognosis. Hypoxia‐inducible factor (HIF) is the master transcriptional regulator mediating hypoxia adaptation and is mainly controlled through proteasomal degradation of its α‐subunit by the ubiquitin–proteasome system (UPS). However, the contribution of deubiquitinases (DUBs) to HIF signalling in PCa remains largely unexplored. Using a computational strategy based on CA9 expression as a surrogate of HIF activity, we identified Ubiquitin‐Specific Protease 29 (USP29) as a key regulator associated with hypoxia and tumour progression and severity in PCa. Mechanistically, USP29 functions as a noncanonical positive regulator of HIF‐α stability in a catalytic‐dependent manner. USP29 interacts with HIF‐1α, reduces its poly‐ubiquitination and protects it from proteasomal degradation across multiple cancer cell lines. Additionally, USP29 stabilizes HIF‐2α acting on the C‐terminal region of HIF‐α. These findings uncover a novel regulatory layer of HIF signalling and highlight USP29 as a potential therapeutic target in hypoxia‐driven PCa progression.

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.

Glycine N-Methyltransferase (GNMT) is a metabolic enzyme that integrates metabolism and epigenetic regulation. The product of GNMT, sarcosine, has been proposed as a prostate cancer biomarker. This enzyme is predominantly expressed in the liver, brain, pancreas, and prostate tissue, where it exhibits distinct regulation. Whereas genetic alterations in GNMT have been associated to prostate cancer risk, its causal contribution to the development of this disease is limited to cell line-based studies and correlative human analyses. Here we integrate human studies, genetic mouse modeling, and cellular systems to characterize the regulation and function of GNMT in prostate cancer. We report that this enzyme is repressed upon activation of the oncogenic Phosphoinositide-3-kinase (PI3K) pathway, which adds complexity to its reported dependency on androgen signaling. Importantly, we demonstrate that expression of GNMT is required for the onset of invasive prostate cancer in a genetic mouse model. Altogether, our results provide further support of the heavy oncogenic signal-dependent regulation of GNMT in prostate cancer.

Nature Communications 8: Article number:15111 (2017); Published: 8 May 2017; Updated: 16 June 2017 The affiliation details for Paula Iruzubieta and Javier Crespo are incorrect in this Article. The correct affiliation details for these authors are given below: Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).

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.

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α–ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment. Torrano et al.  use bioinformatics analyses to identify PGC1α as a transcriptional regulator of a metabolic program downstream of ERRα that opposes metastatic dissemination in prostate cancer.