Oncometabolic Nuclear Reprogramming of Cancer Stemness

Menendez, Javier A.; Corominas-Faja, Bruna; Cuyàs, Elisabet; García, María González; Fernández-Arroyo, Salvador; Fernández, Agustín F.; Joven, Jorge; Fraga, Mario F.; Alarcón, Tomás

doi:10.1016/j.stemcr.2015.12.012

Cited by 33 publications

(41 citation statements)

References 48 publications

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“…Recently studies have demonstrated that a subpopulation of cancer cells, often referred to as cancer stem cells (CSCs) or tumor initiating cells (TICs) [5], is capable of extensive proliferation, self-renewal, and increased frequency of tumor initiation [6]. Gastric CSCs can be enriched with several defined markers, including CD44, aldehyde dehydrogenase (ALDH), and Lgr5 [7,8].…”

Section: Introductionmentioning

confidence: 99%

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Hu¹,

Song²,

Yao³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Gastric cancer is a highly aggressive tumor containing cancer stem cells (CSCs), which participate in tumor initiation, therapeutic resistance, and tumor relapse. Proline-rich protein 11 (PRR11) has been shown to be up-regulated in human cancers; however, its role in gastric CSCs is unknown. We hypothesize that PRR11 may affect tumorigenicity of gastric CSCs. In this study, we explored the biological function and regulation of PRR11 in gastric CSCs. Methods: Expression of PRR11 was evaluated in gastric CSC cell line by real-time quantitative PCR and western blot. The effect of PRR11 on tumorigenicity was examined by interference with gene expression using lentiviral vector-loaded shRNA. A xenograft tumor model using NOD/SCID mice was established to examine the role of PRR11 in tumor development. Results: Data showed that PRR11 was highly expressed in gastric CSCs. PRR11 was responsible for the maintenance of self-renewal and tumorigenicity of gastric CSCs, and overexpression of exogenous PRR11 could restore the self-renewal of gastric non-CSCs. Furthermore, interference with PRR11 altered the expression of stemness transcription factors. Interestingly, MAPK signaling controlled PRR11 expression by increasing PRR11 protein stability, and maintained gastric CSCs self-renewal in a PRR11 dependent manner. Conclusions: PRR11 regulated self-renewal and tumorigenicity of gastric CSCs through MAPK signaling, and could be used as a therapeutic target for gastric cancer.

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Section: Introductionmentioning

confidence: 99%

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Hu¹,

Song²,

Yao³

et al. 2018

Cell Physiol Biochem

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“…3,4,[7][8][9][10][11] Although it remains intriguing how aging-related changes in cellular metabolism might control the layers of epigenetic instructions that influence cell fate without altering the primary DNA sequence, it should be acknowledged that the multiple processes involved in the alteration of the chromatin state, including post-translational modifications of histone proteins, incorporation of specific histone variants, methylation of DNA and ATP-dependent chromatin remodeling, are likely the pivotal molecular bridges that mediate the direct communication between the metabolic and the chromatin state, and the consequent epigenetic targeting of cell fate regulatory genes. [12][13][14][15][16][17][18][19][20] Indeed, because the usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics, one can envision that the spatio-temporal distribution of the levels and types of specific metabolites might operate as key cancer-related molecular events, rendering a cell susceptible to the epigenetic rewiring required for the acquisition of an aberrant cancer cell state and, concurrently, of refractoriness to normal differentiation.…”

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confidence: 99%

Metformin targets histone acetylation in cancer-prone epithelial cells

et al. 2016

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The usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics. Because this metabolism-epigenetics axis can regulate not only normal but also diseased states, it is reasonable to suggest that manipulating the epigenome via metabolic interventions may improve the clinical manifestation of age-related diseases including cancer. Using a model of BRCA1 haploinsufficiency-driven accelerated geroncogenesis, we recently tested the hypothesis that: 1.) metabolic rewiring of the mitochondrial biosynthetic nodes that overproduce epigenetic metabolites such as acetyl-CoA should promote cancer-related acetylation of histone H3 marks; 2.) metformin-induced restriction of mitochondrial biosynthetic capacity should manifest in the epigenetic regulation of histone acetylation. We now provide one of the first examples of how metformin-driven metabolic shifts such as reduction of the 2-carbon epigenetic substrate acetyl-CoA is sufficient to correct specific histone H3 acetylation marks in cancer-prone human epithelial cells. The ability of metformin to regulate mitonuclear communication and modulate the epigenetic landscape in genomically unstable pre-cancerous cells might guide the development of new metabolo-epigenetic strategies for cancer prevention and therapy. KEYWORDS BRCA1; epigenetics; histone acetylation; metformin; mitochondria While metabolic rewiring of cancer cells can be a direct consequence of the concerted action of oncogenes and tumor suppressor genes that drive aberrant growth of cancer tissues, altered metabolism might also play a primary, causative role in oncogenesis. Accordingly, metabolic reprogramming is increasingly appreciated as a candidate hallmark of tumorigenesis. [1][2][3][4][5] In a recently proposed metabolism-centered model of carcinogenesis, known as geroncogenesis 2 the possibility of acquiring genetic aberrations increases when aging itself operates as a driver of cancer-like metabolic landscapes. Tumor formation might therefore depend not only on accumulating mutations in the genome, but also on the decline in the homeostasis or metabolic health that naturally occurs in aging cells. Indeed, after many years of being subordinated to the nucleus as the commander-in-chief, able to initiate biological events, the capacity of metabolism to independently dictate cellular actions is increasingly recognized among most cell biologists. Accordingly, the research community now acknowledges that aging-driven alteration of metabolic homeostasis might be sufficient to favor an imbalance in self-amplifying metabolic landscapes that ultimately manifest as aging-driven diseases, including cancer. 6Metabolic programs: From anabolic supporters of genomic instability to epigenetic regulators of carcinogenesisThe metabolic health of our cells might be a key determinant factor pushing the risk balance or cancer risk-meter toward health or the risk of cancer.1,2 On the one hand, genomic instability, a charac...

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“…Such epigenetic control is often 151 related to alternative covalent modifications of histones. To address the high complexity 152 of ER, we focus on a simpler stochastic model of ER, based on that formulated 153 in [13,18] and [19]. Our model belongs to a wider class of models which consider that Evolution to the silenced state of the pluripotency-regulating gene.…”

Section: Introduction 25mentioning

confidence: 99%

A multiscale model of epigenetic heterogeneity reveals the kinetic routes of pathological cell fate reprogramming

Folguera-Blasco

Pérez-Carrasco

Cuyàs

et al. 2018

Preprint

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The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. Furthermore, based on the existence of multiple scales, we formulate a method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme that allows us to deal with such complex systems. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We then formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (pluripotent stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validated the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming from pathological to physiological might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer. Author summaryCertain modifications of the structure and functioning of the protein/DNA complex 1 called chromatin can allow adult, fully differentiated cells to adopt a stem cell-like 2 pluripotent state in a purely epigenetic manner, not involving changes in the underlying 3 DNA sequence. Such reprogramming-like phenomena may constitute an innate 4 reparative route through which human tissues respond to injury and could also serve as 5 a novel regenerative strategy in human pathological situations in which tissue or organ 6 repair is impaired. However, it should be noted that in vivo reprogramming would be 7 capable of maintaining tissue homeostasis provided the acquisition of pluripotency 8 features is strictly transient and accompanied by an accurate replenishment of the 9 specific cell types being lost. Crucially, an excessive reprogramming to pluripotency in 10 the absence of controlled re-differentiation would impair the repair or the replacement of 11 damaged cells, thereby promoting pathological alterations of cell fate. A mechanistic 12 understanding of how the degree of chromatin plasticity dictates the reparative versus 13 pathological behaviour of in vivo reprogramming to rejuvenate aged tissues while 14 preventing tumorigenesis is urgently needed, including especially th...

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Oncometabolic Nuclear Reprogramming of Cancer Stemness

Cited by 33 publications

References 48 publications

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Metformin targets histone acetylation in cancer-prone epithelial cells

A multiscale model of epigenetic heterogeneity reveals the kinetic routes of pathological cell fate reprogramming

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