Abstract Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a bona fide tumor ...suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic hit. OIS is often characterized by aberrant DNA replication and the associated DNA damage response. Nucleotides, in particular deoxyribonucleotide triphosphates (dNTPs), are necessary for both DNA replication and repair. Imbalanced dNTP pools play a role in a number of human diseases, including during the early stages of cancer development. This review will highlight what is currently known about the role of decreased nucleotide metabolism in OIS, how nucleotide metabolism leads to transformation and tumor progression, and how this pathway can be targeted as a cancer therapeutic by inducing senescence of cancer cells.
Oncogene-induced senescence is characterized by a stable cell growth arrest, thus providing a tumor suppression mechanism. However, the underlying mechanisms for this phenomenon remain unknown. Here, ...we show that a decrease in deoxyribonucleotide triphosphate (dNTP) levels underlies oncogene-induced stable senescence-associated cell growth arrest. The decrease in dNTP levels is caused by oncogene-induced repression of ribonucleotide reductase subunit M2 (RRM2), a rate-limiting protein in dNTP synthesis. This precedes the senescence-associated cell-cycle exit and coincides with the DNA damage response. Consistently, RRM2 downregulation is both necessary and sufficient for senescence. Strikingly, suppression of nucleotide metabolism by RRM2 repression is also necessary for maintenance of the stable senescence-associated cell growth arrest. Furthermore, RRM2 repression correlates with senescence status in benign nevi and melanoma, and its knockdown drives senescence of melanoma cells. These data reveal the molecular basis whereby the stable growth arrest of oncogene-induced senescence is established and maintained through suppression of nucleotide metabolism.
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► Addition of exogenous nucleosides reverses the senescence-associated cell growth arrest ► RRM2 repression drives the decrease in dNTP levels to promote senescence ► RRM2 repression is both necessary and sufficient for senescence ► RRM2 repression correlates with melanocyte senescence status in nevi and melanoma
Oncogene-induced senescence (OIS) suppresses tumorigenesis by driving a stable cell growth arrest. However, the molecular mechanism underlying this phenomenon remains unclear. Zhang and colleagues demonstrate that suppression of nucleotide metabolism via RRM2 repression underlies the establishment and maintenance of the stable cell growth arrest, which establishes OIS as an important tumor suppression mechanism. These data reveal the molecular basis through which stable OIS-associated cell growth arrest is established and maintained.
Abstract Ovarian cancer is the most lethal gynecological malignancy and is often associated with both DNA repair deficiency and extensive metabolic reprogramming. While still emerging, the interplay ...between these pathways can affect ovarian cancer phenotypes, including therapeutic resistance to the DNA damaging agents that are standard‐of‐care for this tumor type. In this review, we will discuss what is currently known about cellular metabolic rewiring in ovarian cancer that may impact DNA damage and repair in addition to highlighting how specific DNA repair proteins also promote metabolic changes. We will also discuss relevant data from other cancers that could be used to inform ovarian cancer therapeutic strategies. Changes in the choice of DNA repair mechanism adopted by ovarian cancer are a major factor in promoting therapeutic resistance. Therefore, the impact of metabolic reprogramming on DNA repair mechanisms in ovarian cancer has major clinical implications for targeted combination therapies for the treatment of this devastating disease.
Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the ...senescence-associated secretory phenotype (SASP). NAD
metabolism influences both tissue ageing and cancer. However, the role of NAD
metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD
salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD
signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD
-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD
metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD
augmentation should be administered with precision.
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which ...currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
One of the most prominent features of cellular senescence, a stress response that prevents the propagation of cells that have accumulated potentially oncogenic alterations, is a permanent loss of ...proliferative potential. Thus, at odds with quiescent cells, which resume proliferation when stimulated to do so, senescent cells cannot proceed through the cell cycle even in the presence of mitogenic factors. Here, we describe a set of cytofluorometric techniques for studying how chemical and/or physical stimuli alter the cell cycle in vitro, in both qualitative and quantitative terms. Taken together, these methods allow for the identification of bona fide cytostatic effects as well as for a refined characterization of cell cycle distributions, providing information on proliferation, DNA content, as well as the presence of cell cycle phase-specific markers. At the end of the chapter, a set of guidelines is offered to assist researchers that approach the study of the cell cycle with the interpretation of results.
The maintenance of a healthy deoxyribonucleotide triphosphate (dNTP) pool is critical for the proper replication and repair of both nuclear and mitochondrial DNA. Temporal, spatial, and ratio ...imbalances of the four dNTPs have been shown to have a mutagenic and cytotoxic effect. It is, therefore, essential for cell homeostasis to maintain the balance between the processes of dNTP biosynthesis and degradation. Multiple oncogenic signaling pathways, such as c-Myc, p53, and mTORC1 feed into dNTP metabolism, and there is a clear role for dNTP imbalances in cancer initiation and progression. Additionally, multiple chemotherapeutics target these pathways to inhibit nucleotide synthesis. Less is understood about the role for dNTP levels in metabolic disorders and syndromes and whether alterations in dNTP levels change cancer incidence in these patients. For instance, while deficiencies in some metabolic pathways known to play a role in nucleotide synthesis are pro-tumorigenic (e.g., p53 mutations), others confer an advantage against the onset of cancer (G6PD). More recent evidence indicates that there are changes in nucleotide metabolism in diabetes, obesity, and insulin resistance; however, whether these changes play a mechanistic role is unclear. In this review, we will address the complex network of metabolic pathways, whereby cells can fuel dNTP biosynthesis and catabolism in cancer, and we will discuss the potential role for this pathway in metabolic disease.
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually ...exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.
Cellular senescence is a stable cell growth arrest that is characterized by the silencing of proliferation-promoting genes through compaction of chromosomes into senescence-associated heterochromatin ...foci (SAHF). Paradoxically, senescence is also accompanied by increased transcription of certain genes encoding for secreted factors such as cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP). How SASP genes are excluded from SAHF-mediated global gene silencing remains unclear. In this study, we report that high mobility group box 2 (HMGB2) orchestrates the chromatin landscape of SASP gene loci. HMGB2 preferentially localizes to SASP gene loci during senescence. Loss of HMGB2 during senescence blunts SASP gene expression by allowing for spreading of repressive heterochromatin into SASP gene loci. This correlates with incorporation of SASP gene loci into SAHF. Our results establish HMGB2 as a novel master regulator that orchestrates SASP through prevention of heterochromatin spreading to allow for exclusion of SASP gene loci from a global heterochromatin environment during senescence.
Molecular therapies are hallmarks of âpersonalizedâ medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol ...3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, âspatiotemporalâ mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.
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