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1.
J Clin Invest ; 132(6)2022 03 15.
Article in English | MEDLINE | ID: mdl-35133980

ABSTRACT

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, containing GBM stem cells (GSCs) that contribute to therapeutic resistance and relapse. Exposing potential GSC vulnerabilities may provide therapeutic strategies against GBM. Here, we interrogated the role of adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase acting on RNA 1 (ADAR1) in GSCs and found that both ADAR1 and global RNA editomes were elevated in GSCs compared with normal neural stem cells. ADAR1 inactivation or blocking of the upstream JAK/STAT pathway through TYK2 inhibition impaired GSC self-renewal and stemness. Downstream of ADAR1, RNA editing of the 3'-UTR of GM2A, a key ganglioside catabolism activator, proved to be critical, as interference with ganglioside catabolism and disruption of ADAR1 showed a similar functional impact on GSCs. These findings reveal that RNA editing links ganglioside catabolism to GSC self-renewal and stemness, exposing a potential vulnerability of GBM for therapeutic intervention.


Subject(s)
Glioblastoma , Neural Stem Cells , RNA-Binding Proteins/metabolism , Adenosine Deaminase/genetics , Gangliosides/metabolism , Glioblastoma/metabolism , Humans , Janus Kinases/genetics , Janus Kinases/metabolism , Neoplasm Recurrence, Local/metabolism , Neoplastic Stem Cells/pathology , Neural Stem Cells/metabolism , RNA , RNA Editing , STAT Transcription Factors , Signal Transduction/genetics
2.
Trends Cancer ; 5(8): 475-494, 2019 08.
Article in English | MEDLINE | ID: mdl-31421905

ABSTRACT

Circadian clocks constitute the evolutionary molecular machinery that dictates the temporal regulation of physiology to maintain homeostasis. Disruption of the circadian rhythm plays a key role in tumorigenesis and facilitates the establishment of cancer hallmarks. Conversely, oncogenic processes directly weaken circadian rhythms. Pharmacological modulation of core clock genes is a new approach in cancer therapy. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, encompassing the prevention, diagnosis, and treatment of this devastating disease. This review highlights the role of the circadian clock in tumorigenesis and cancer hallmarks, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinogenesis/drug effects , Circadian Clocks/drug effects , Homeostasis/drug effects , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Carcinogenesis/genetics , Carcinogenesis/pathology , Circadian Clocks/genetics , Circadian Clocks/physiology , Circadian Rhythm/physiology , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/physiology , Homeostasis/physiology , Humans , Neoplasms/genetics , Neoplasms/physiopathology
3.
Trends Pharmacol Sci ; 39(9): 812-827, 2018 09.
Article in English | MEDLINE | ID: mdl-30060890

ABSTRACT

Daily rhythms in behavior, physiology, and metabolism are an integral part of homeostasis. These rhythms emerge from interactions between endogenous circadian clocks and ambient light-dark cycles, sleep-activity cycles, and eating-fasting cycles. Nearly the entire primate genome shows daily rhythms in expression in tissue- and locus-specific manners. These molecular rhythms modulate several key aspects of cellular and tissue function with profound implications in public health, disease prevention, and disease management. In modern societies light at night disrupts circadian rhythms, leading to further disruption of sleep-activity and eating-fasting cycles. While acute circadian disruption may cause transient discomfort or exacerbate chronic diseases, chronic circadian disruption can enhance risks for numerous diseases. The molecular understanding of circadian rhythms is opening new therapeutic frontiers placing the circadian clock in a central role. Here, we review recent advancements on how to enhance our circadian clock through behavioral interventions, timing of drug administration, and pharmacological targeting of circadian clock components that are already providing new preventive and therapeutic strategies for several diseases, including metabolic syndrome and cancer.


Subject(s)
Chronic Disease/therapy , Circadian Clocks/drug effects , Circadian Clocks/physiology , Drug Chronotherapy , Animals , Drug Administration Schedule , Humans
4.
Nature ; 553(7688): 351-355, 2018 01 18.
Article in English | MEDLINE | ID: mdl-29320480

ABSTRACT

The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer and chronic circadian rhythm disruption predisposes individuals to tumour development. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBß (also known as NR1D2), are essential components of the circadian clock. Here we show that two agonists of REV-ERBs-SR9009 and SR9011-are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and have no effect on the viability of normal cells or tissues. The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as HRAS, BRAF, PIK3CA and others) and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 has a critical role in evoking an apoptotic response in malignant cells. Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is an effective antitumour strategy, identifying a class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are inhibitors of autophagy and de novo lipogenesis, with selective activity towards malignant and benign neoplasms.


Subject(s)
Neoplasms/drug therapy , Neoplasms/pathology , Nuclear Receptor Subfamily 1, Group D, Member 1/agonists , Oncogenes/genetics , Animals , Apoptosis/drug effects , Autophagy/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Circadian Clocks/genetics , Circadian Clocks/physiology , Female , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Glioblastoma/drug therapy , Glioblastoma/pathology , Humans , Lipogenesis/drug effects , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice, Inbred C57BL , Neoplasms/genetics , Nevus/drug therapy , Nevus/pathology , Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism , Pyrrolidines/pharmacology , Signal Transduction/drug effects , Thiophenes/pharmacology
5.
Nat Rev Cancer ; 12(10): 709-20, 2012 10.
Article in English | MEDLINE | ID: mdl-22952011

ABSTRACT

The generation of DNA lesions and the resulting activation of DNA damage response (DDR) pathways are both affected by the chromatin status at the site of damaged DNA. In turn, DDR activation affects the chromatin at both the damaged site and across the whole genome. Cellular senescence and cancer are associated with the engagement of the DDR pathways and with profound chromatin changes. In this Opinion article, we discuss the interplay between chromatin and DDR factors in the context of cellular senescence that is induced by oncogenes and in cancer.


Subject(s)
Cellular Senescence/genetics , Chromatin/metabolism , DNA Repair , Neoplasms/genetics , Animals , DNA/metabolism , DNA Damage , Histones/metabolism , Humans , Signal Transduction
6.
Nat Cell Biol ; 13(3): 292-302, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21336312

ABSTRACT

Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16(INK4a) induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours.


Subject(s)
Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA Damage , Heterochromatin/genetics , Neoplasms/metabolism , Oncogenes , Animals , Apoptosis , Cell Line, Tumor , Chromatin/metabolism , DNA Replication , Histone Deacetylase Inhibitors/pharmacology , Humans , Mice , Microscopy, Fluorescence/methods , Neoplasm Transplantation , Plasmids/metabolism , RNA, Small Interfering/metabolism
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