circRNAs arise from back splicing events during mRNA processing, and when deregulated can play an active role in cancer. Here we characterize a new circRNA (circPOK) encoded by the Zbtb7a gene (also ...kown as POKEMON, LRF) in the context of mesenchymal tumor progression. circPOK functions as a non-coding proto-oncogenic RNA independently and antithetically to its linear transcript counterpart, which acts as a tumor suppressor by encoding the Pokemon transcription factor. We find that circPOK regulates pro-proliferative and pro-angiogenic factors by co-activation of the ILF2/3 complex. Importantly, the expression of Pokemon protein and circRNA is aberrantly uncoupled in cancer through differential post-transcriptional regulation. Thus, we identify a novel type of genetic unit, the iRegulon, that yields biochemically distinct RNA products, circular and linear, with diverse and antithetical functions. Our findings further expand the cellular repertoire towards the control of normal biological outputs, while aberrant expression of such components may underlie disease pathogenesis including cancer.
A circular twist on microRNA regulation Bezzi, Marco; Guarnerio, Jlenia; Pandolfi, Pier Paolo
Cell research,
12/2017, Letnik:
27, Številka:
12
Journal Article
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Circular RNAs （circRNAs） are a novel class of RNA whose physiological function has yet to be investigated. A recent publication in Science provides the first evidence of the biological relevance of a ...circRNA in an in vivo model and unveils an unexpected twist on their crosstalk with miRNAs.
Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect ...non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.
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•F-circRNAs are generated from cancer-associated chromosomal translocations•F-circRNAs promote transformation and cell survival upon treatment•F-circRNAs confer resistance to treatment in tumor cells
Chromosomal translocations associated with cancer give rise to fusion circRNAs which contribute to cellular transformation, affect cell viability, and have tumor-promoting properties in in vivo models.
Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To ...date, most studies have focused on tumor-intrinsic properties that render them "immune-excluded". Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E
(PGE
) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE
release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This "iDAMP blockade" approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.
Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well ...understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.
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•Commensal bacteria support antitumor T cell responses following radiation therapy•Depletion of intestinal bacteria leads to expansion of commensal fungal populations•Commensal fungi promote pro-tumor macrophage actions by impeding antitumor T cells•Tumor-associated macrophages sense fungi through a Dectin-1-mediated mechanism
Depletion of commensal bacteria leads to expansion of commensal fungi and reduced antitumor immunity following irradiation of tumors. Targeting commensal fungi enhanced the radiation-induced antitumor immune response by reducing macrophage-mediated immunosuppression. Thus, Shiao et al. demonstrate opposing effects of commensal bacteria and fungi on antitumor immunity following radiation.
A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for ...inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical ...evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.
PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here, we show that PTEN homodimerizes and, in this active conformation, exerts lipid phosphatase activity ...on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants heterodimerize with wild-type PTEN and constrain its phosphatase activity in a dominant-negative manner. To study the consequences of homo- and heterodimerization of wild-type and mutant PTEN in vivo, we generated Pten knockin mice harboring two cancer-associated PTEN mutations (PtenC124S and PtenG129E). Heterozygous PtenC124S/+ and PtenG129E/+ cells and tissues exhibit increased sensitivity to PI3-K/Akt activation compared to wild-type and Pten+/− counterparts, whereas this difference is no longer apparent between PtenC124S/− and Pten−/− cells. Notably, Pten KI mice are more tumor prone and display features reminiscent of complete Pten loss. Our findings reveal that PTEN loss and PTEN mutations are not synonymous and define a working model for the function and regulation of PTEN.
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•PTEN exists in an active, unphosphorylated dimeric conformation•PTEN missense mutations exert dominant-negative effects over the wild-type protein•Pten mutations elicit Akt hyperactivation and augmented tumorigenesis in the mouse•Mutant PTEN associates with increased AKT phosphorylation in human cancer
PTEN functions as a dimer, and cancer-associated PTEN mutants can act in a dominant-negative manner by heterodimerizing with and inhibiting the wild-type protein, revealing a tumorigenic and signaling mechanism for this well-known tumor suppressor.
Circular RNAs (circRNAs) are regulatory RNAs which have recently been shown to have clinical significance in several diseases, including, but not limited to, various cancers, neurological diseases ...and cardiovascular diseases. The function of such regulatory RNAs is largely dependent on their subcellular localization. Several circRNAs have been shown to conduct antagonistic roles compared to the products of the linear isoforms, and thus need to be characterized distinctly from the linear RNAs. However, conventional fluorescent in situ hybridization (FISH) techniques cannot be employed directly to distinguish the signals from linear and circular isoforms because most circRNAs share the same sequence with the linear RNAs. In order to address this unmet need, we adapted the well-established method of single-molecule FISH by designing two sets of probes to differentiate the linear and circular RNA isoforms by virtue of signal colocalization. We call this method 'circular fluorescent in situ hybridization' (circFISH). Linear and circular RNAs were successfully visualized and quantified at a single-molecule resolution in fixed cells. RNase R treatment during the circFISH reduced the levels of linear RNAs while the circRNA levels remain unaltered. Furthermore, cells with shRNAs specific to circRNA showed the loss of circRNA levels, whereas the linear RNA levels were unaffected. The optimization of the in-situ RNase R treatment allowed the multiplexing of circFISH to combine it with organelle staining. CircFISH was found to be compatible with multiple sample types, including cultured cells and fresh-frozen and formalin-fixed tissue sections. Thus, we present circFISH as a versatile method for the simultaneous visualization and quantification of the distribution and localization of linear and circular RNA in fixed cells and tissue samples.
While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways ...that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.
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•Prolyl hydroxylase 3 (PHD3) hydroxylates and activates the metabolic enzyme ACC2•During nutrient abundance, the PHD3/ACC2 axis represses fatty acid oxidation (FAO)•PHD3 is low in AML, fueling a reliance on fats that can be targeted with FAO inhibitors•Re-expressing PHD3 limits FAO via ACC2 and suppresses AML in culture and in vivo
Fatty acid oxidation (FAO) fuels the growth of many cancers. German et al. show that prolyl hydroxylase 3 (PHD3) inhibits nutrient-dependent FAO by activating ACC2 and blocking mitochondrial fatty acid import. PHD3 levels are decreased in acute myeloid leukemia, promoting FAO and a metabolic dependency, which can be targeted pharmacologically.
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