Interplay between Circadian Clock and Cancer: New Frontiers for Cancer Treatment

Trends in cancer, Journal Year: 2019, Volume and Issue: 5(8), P. 475 - 494

Published: Aug. 1, 2019

Language: Английский

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Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression

Nature Immunology, Journal Year: 2019, Volume and Issue: 20(7), P. 835 - 851

Published: June 3, 2019

Language: Английский

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Expression profile of immune checkpoint genes and their roles in predicting immunotherapy response

Briefings in Bioinformatics, Journal Year: 2020, Volume and Issue: 22(3)

Published: July 15, 2020

Abstract Immune checkpoint genes (ICGs) play critical roles in circumventing self-reactivity and represent a novel target to develop treatments for cancers. However, comprehensive analysis the expression profile of ICGs at pan-cancer level their correlation with patient response immune blockade (ICB) based therapy is still lacking. In this study, we defined three patterns using survey RNA-seq data tumor cells from functional annotation mammalian genome (FANTOM5) project. The between patients survival ICB was investigated. were robust across cancers, upregulation positively correlated high lymphocyte infiltration good prognosis. Furthermore, built model (ICGe) predict five features ICG expression. A validation scenario six independent datasets containing 261 CTLA-4 PD-1 immunotherapies demonstrated that ICGe achieved area under curves 0.64–0.82 showed performance outperformed other mRNA-based predictors. conclusion, work revealed underlying correlations ICB, which helps understand mechanisms signal pathways anticancer treatments.

Language: Английский

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Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

Cancer Discovery, Journal Year: 2019, Volume and Issue: 9(11), P. 1556 - 1573

Published: Aug. 27, 2019

Abstract Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSC). Here, we show that GSCs, differentiated (DGC), and nonmalignant brain cultures all displayed robust circadian rhythms, yet GSCs alone exquisite dependence on core clock transcription factors, BMAL1 CLOCK, for optimal cell growth. Downregulation of or CLOCK in induced cell-cycle arrest apoptosis. Chromatin immunoprecipitation revealed preferentially bound metabolic genes was associated with active chromatin regions compared neural cells. Targeting attenuated mitochondrial function reduced expression tricarboxylic acid cycle enzymes. Small-molecule agonists two independent BMAL1–CLOCK negative regulators, the cryptochromes REV-ERBs, downregulated factors GSC Combination cryptochrome REV-ERB synergistic antitumor efficacy. Collectively, these findings co-opt regulators beyond canonical circuitry to promote stemness maintenance metabolism, offering novel therapeutic paradigms. Significance: Cancer malignant tumor-cell populations. We demonstrate selectively depend increased binding promoting tumor metabolism. Supporting clinical relevance, pharmacologic targeting networks specifically disrupted cancer growth self-renewal. This article is highlighted In Issue feature, p. 1469

Language: Английский

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Molecular regulations of circadian rhythm and implications for physiology and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 8, 2022

The term "circadian rhythms" describes endogenous oscillations with ca. 24-h period associated the earth's daily rotation and light/dark cycle. Such rhythms reflect existence of an intrinsic circadian clock that temporally orchestrates physiological processes to adapt internal environment external cues. At molecular level, consists multiple sets transcription factors resulting in autoregulatory transcription-translation feedback loops. Notably, addition their primary role as generator rhythm, biological plays a key controlling functions almost all tissues organs. It regulates several intracellular signaling pathways, ranging from cell proliferation, DNA damage repair response, angiogenesis, metabolic redox homeostasis, inflammatory immune response. In this review, we summarize findings showing crosstalk between some describing scenario wherein reciprocal regulation impinges upon aspects mammalian physiology. Moreover, based on evidence indicating can be challenged by environmental factors, social behaviors, well pre-existing pathological conditions, discuss implications misalignment human pathologies, such cancer diseases. Accordingly, disruption rhythm has been reported affect are relevant Expanding our understanding field represents intriguing transversal medicine challenge order establish precision medicine.

Language: Английский

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Clocks, cancer, and chronochemotherapy

Science, Journal Year: 2020, Volume and Issue: 371(6524)

Published: Dec. 31, 2020

Doubts in cancer-rhythms connections Circadian clocks help to coordinate physiological processes with the daily cycles of light and dark periods feeding, activity, rest. Being out sync such 24-hour can have unhealthy effects. Sancar Van Gelder review available evidence regarding circadian disruption predisposition cancer variations response chemotherapy. The literature be difficult interpret. For example, complete knockouts clock genes are not same as shift work. Overall, they find that jury is still on whether promote general if timing treatment optimized. However, enough indications present further research recommended. Science , this issue p. 42

Language: Английский

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Transcriptional landscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 8, 2019

Enhancer RNA (eRNA) is a type of noncoding transcribed from the enhancer. Although critical roles eRNA in gene transcription control have been increasingly realized, systemic landscape and potential function eRNAs cancer remains largely unexplored. Here, we report integration multi-omics pharmacogenomics data across large-scale patient samples cell lines. We observe cancer-/lineage-specificity eRNAs, which may be driven by tissue-specific TFs. are involved multiple signaling pathways through putatively regulating their target genes, including clinically actionable genes immune checkpoints. They also affect drug response within-pathway or cross-pathway means. characterize oncogenic therapeutic liability one eRNA, NET1e, supporting clinical feasibility eRNA-targeted therapy. identify panel relevant developed user-friendly portal. Our study reveals transcriptional utility cancer.

Language: Английский

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Characterization of hypoxia-associated molecular features to aid hypoxia-targeted therapy

Nature Metabolism, Journal Year: 2019, Volume and Issue: 1(4), P. 431 - 444

Published: March 18, 2019

Language: Английский

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Metabolic and cardiovascular consequences of shift work: The role of circadian disruption and sleep disturbances

European Journal of Neuroscience, Journal Year: 2018, Volume and Issue: 51(1), P. 396 - 412

Published: Oct. 25, 2018

Abstract Shift work, defined as work occurring outside typical daytime working hours, is associated with an increased risk of various non‐communicable diseases, including diabetes and cardiovascular disease. Disruption the internal circadian timing system concomitant sleep disturbances thought to play a critical role in development these health problems. Indeed, controlled laboratory studies have shown that short‐term misalignment restriction independently impair physiological processes, insulin sensitivity, energy expenditure, immune function, blood pressure cardiac modulation by autonomous nervous system. If allowed persist, acute effects may lead cardiometabolic diseases long term. Here, we discuss evidence for contributions disruption metabolic problems shift workers. Improving understanding mechanisms affected disturbance will contribute implementation strategies prevent or mitigate impact work.

Language: Английский

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Comprehensive characterization of circular RNAs in ~ 1000 human cancer cell lines

Genome Medicine, Journal Year: 2019, Volume and Issue: 11(1)

Published: Aug. 25, 2019

Human cancer cell lines are fundamental models for research and therapeutic strategy development. However, there is no characterization of circular RNAs (circRNAs) in a large number lines.Here, we apply four circRNA identification algorithms to heuristically characterize the expression landscape circRNAs across ~ 1000 human from CCLE polyA-enriched RNA-seq data. By using integrative analysis experimental approaches, explore landscape, biogenesis, functional consequences, drug response different lineages.We revealed highly lineage-specific patterns circRNAs, suggesting that may be powerful diagnostic and/or prognostic markers treatment. We also identified key genes involved biogenesis confirmed TGF-β signaling promote circRNAs. Strikingly, showed clinically actionable more likely generate potentially due enrichment RNA-binding protein (RBP) binding sites. Among these, circMYC can proliferation. observed strong association between drugs, especially those targeting chromatin histone acetylation. Finally, developed user-friendly data portal, CircRNAs (CircRiC, https://hanlab.uth.edu/cRic ), benefit biomedical community.Our study provides explored potential mechanism as well its implications. provide portal facilitate related researches.

Language: Английский

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