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Cell Metabolism Sep 2023In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the...
In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.
Topics: Humans; Animals; Histones; Glycolysis; Cell Proliferation; Colorectal Neoplasms; Lactates; Diapause; Adenosine Triphosphatases; Chromosomal Proteins, Non-Histone
PubMed: 37543034
DOI: 10.1016/j.cmet.2023.07.005 -
Cell Metabolism Sep 2023Just like time and tide, embryonic development waits for no man but progresses forcefully to its completion, with just one exception. Diapause is an enigmatic,...
Just like time and tide, embryonic development waits for no man but progresses forcefully to its completion, with just one exception. Diapause is an enigmatic, reversible, dormant halt that protects the developing embryo. Cancer cells have evolved to hijack many useful stem cell capabilities, and diapause is no exception. Recent work has revealed a diapause-like cancer cell state, prompting the quest for its key molecular regulators useful for cancer therapies. The present paper by Sun et al. addresses this knowledge gap by revealing a key player in regulating the diapause-like cancer cell stage, the condensin protein SMC4.
Topics: Female; Pregnancy; Humans; Embryo, Mammalian; Embryonic Development; Stem Cells
PubMed: 37673033
DOI: 10.1016/j.cmet.2023.08.007 -
Nature Cell Biology Aug 2023Cellular reprogramming by only small molecules holds enormous potentials for regenerative medicine. However, chemical reprogramming remains a slow process and labour...
Cellular reprogramming by only small molecules holds enormous potentials for regenerative medicine. However, chemical reprogramming remains a slow process and labour intensive, hindering its broad applications and the investigation of underlying molecular mechanisms. Here, through screening of over 21,000 conditions, we develop a fast chemical reprogramming (FCR) system, which significantly improves the kinetics of cell identity rewiring. We find that FCR rapidly goes through an interesting route for pluripotent reprogramming, uniquely transitioning through a developmentally diapause-like state. Furthermore, FCR critically enables comprehensive characterizations using multi-omics technologies, and has revealed unexpected important features including key regulatory factors and epigenetic dynamics. Particularly, activation of pluripotency-related endogenous retroviruses via inhibition of heterochromatin significantly enhances reprogramming. Our studies provide critical insights into how only environmental cues are sufficient to rapidly reinstate pluripotency in somatic cells, and make notable technical and conceptual advances for solving the puzzle of regeneration.
Topics: Animals; Pluripotent Stem Cells; Cellular Reprogramming; Cellular Reprogramming Techniques; Regenerative Medicine; Diapause; Induced Pluripotent Stem Cells
PubMed: 37550515
DOI: 10.1038/s41556-023-01193-x -
Biochemical Society Transactions Oct 2023Diapause is a protective mechanism that many organisms deploy to overcome environmental adversities. Diapause extends lifespan and fertility to enhance the reproductive... (Review)
Review
Diapause is a protective mechanism that many organisms deploy to overcome environmental adversities. Diapause extends lifespan and fertility to enhance the reproductive success and survival of the species. Although diapause states have been known and employed for commercial purposes, for example in the silk industry, detailed molecular and cell biological studies are an exciting frontier. Understanding diapause-like protective mechanisms will shed light on pathways that steer organisms through adverse conditions. One hope is that an understanding of the mechanisms that support diapause might be leveraged to extend the lifespan and/or health span of humans as well as species threatened by climate change. In addition, recent findings suggest that cancer cells that persist after treatment mimic diapause-like states, implying that these programs may facilitate cancer cell survival from chemotherapy and cause relapse. Here, we review the molecular mechanisms underlying diapause programs in a variety of organisms, and we discuss pathways supporting diapause-like states in tumor persister cells.
Topics: Animals; Humans; Diapause; Reproduction; Longevity
PubMed: 37800560
DOI: 10.1042/BST20221431 -
Nature Cell Biology Sep 2023Embryos across metazoan lineages can enter reversible states of developmental pausing, or diapause, in response to adverse environmental conditions. The molecular...
Embryos across metazoan lineages can enter reversible states of developmental pausing, or diapause, in response to adverse environmental conditions. The molecular mechanisms that underlie this remarkable dormant state remain largely unknown. Here we show that N-methyladenosine (mA) RNA methylation by Mettl3 is required for developmental pausing in mouse blastocysts and embryonic stem (ES) cells. Mettl3 enforces transcriptional dormancy through two interconnected mechanisms: (1) it promotes global mRNA destabilization and (2) it suppresses global nascent transcription by destabilizing the mRNA of the transcriptional amplifier and oncogene N-Myc, which we identify as a crucial anti-pausing factor. Knockdown of N-Myc rescues pausing in Mettl3 ES cells, and forced demethylation and stabilization of Mycn mRNA in paused wild-type ES cells largely recapitulates the transcriptional defects of Mettl3 ES cells. These findings uncover Mettl3 as a key orchestrator of the crosstalk between transcriptomic and epitranscriptomic regulation during developmental pausing, with implications for dormancy in adult stem cells and cancer.
Topics: Animals; Mice; Adult Stem Cells; Blastocyst; Embryonic Stem Cells; Methylation; RNA, Messenger
PubMed: 37696947
DOI: 10.1038/s41556-023-01212-x -
Trends in Ecology & Evolution May 2024Insects have major impacts on forest ecosystems, from herbivory and soil-nutrient cycling to killing trees at a large scale. Forest insects from temperate, tropical, and... (Review)
Review
Insects have major impacts on forest ecosystems, from herbivory and soil-nutrient cycling to killing trees at a large scale. Forest insects from temperate, tropical, and subtropical regions have evolved strategies to respond to seasonality; for example, by entering diapause, to mitigate adversity and to synchronize lifecycles with favorable periods. Here, we show that distinct functional groups of forest insects; that is, canopy dwellers, trunk-associated species, and soil/litter-inhabiting insects, express a variety of diapause strategies, but do not show systematic differences in diapause strategy depending on functional group. Due to the overall similarities in diapause strategies, we can better estimate the impacts of anthropogenic change on forest insect populations and, consequently, on key ecosystems.
PubMed: 38777634
DOI: 10.1016/j.tree.2024.04.010 -
MedComm Dec 2023Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share... (Review)
Review
Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.
PubMed: 38045829
DOI: 10.1002/mco2.427 -
Insect Biochemistry and Molecular... Sep 2023The fat body is responsible for a variety of functions related to energy metabolism in arthropods, by controlling the processes of de novo glucose production... (Review)
Review
The fat body is responsible for a variety of functions related to energy metabolism in arthropods, by controlling the processes of de novo glucose production (gluconeogenesis) and glycogen metabolism. The rate-limiting factor of gluconeogenesis is the enzyme phosphoenolpyruvate carboxykinase (PEPCK), generally considered to be the first committed step in this pathway. Although the study of PEPCK and gluconeogenesis has been for decades restricted to mammalian models, especially focusing on muscle and liver tissue, current research has demonstrated particularities about the regulation of this enzyme in arthropods, and described new functions. This review will focus on arthropod PEPCK, discuss different aspects to PEPCK regulation and function, its general role in the regulation of gluconeogenesis and other pathways. The text also presents our views on potentially important new directions for research involving this enzyme in a variety of metabolic adaptations (e.g. diapause), discussing enzyme isoforms, roles during arthropod embryogenesis, as well as involvement in vector-pathogen interactions, contributing to a better understanding of insect vectors of diseases and their control.
Topics: Animals; Arthropods; Phosphoenolpyruvate Carboxykinase (GTP); Phosphoenolpyruvate Carboxykinase (ATP); Glucose; Homeostasis; Mammals
PubMed: 37454751
DOI: 10.1016/j.ibmb.2023.103986 -
The Journal of Comparative Neurology Oct 2023Insects from high latitudes spend the winter in a state of overwintering diapause, which is characterized by arrested reproduction, reduced food intake and metabolism,...
Insects from high latitudes spend the winter in a state of overwintering diapause, which is characterized by arrested reproduction, reduced food intake and metabolism, and increased life span. The main trigger to enter diapause is the decreasing day length in summer-autumn. It is thus assumed that the circadian clock acts as an internal sensor for measuring photoperiod and orchestrates appropriate seasonal changes in physiology and metabolism through various neurohormones. However, little is known about the neuronal organization of the circadian clock network and the neurosecretory system that controls diapause in high-latitude insects. We addressed this here by mapping the expression of clock proteins and neuropeptides/neurohormones in the high-latitude fly Drosophila littoralis. We found that the principal organization of both systems is similar to that in Drosophila melanogaster, but with some striking differences in neuropeptide expression levels and patterns. The small ventrolateral clock neurons that express pigment-dispersing factor (PDF) and short neuropeptide F (sNPF) and are most important for robust circadian rhythmicity in D. melanogaster virtually lack PDF and sNPF expression in D. littoralis. In contrast, dorsolateral clock neurons that express ion transport peptide in D. melanogaster additionally express allatostatin-C and appear suited to transfer day-length information to the neurosecretory system of D. littoralis. The lateral neurosecretory cells of D. littoralis contain more neuropeptides than D. melanogaster. Among them, the cells that coexpress corazonin, PDF, and diuretic hormone 44 appear most suited to control diapause. Our work sets the stage to investigate the roles of these diverse neuropeptides in regulating insect diapause.
Topics: Animals; Drosophila; Drosophila melanogaster; CLOCK Proteins; Circadian Rhythm; Diapause; Circadian Clocks; Neuropeptides; Drosophila Proteins
PubMed: 37493077
DOI: 10.1002/cne.25522 -
Insects Apr 2024The aphidophagous gall midge, (Rondani) (Diptera: Cecidomyiidae), a dominant natural enemy of aphids, has been used as a biological control agent in many countries to...
The aphidophagous gall midge, (Rondani) (Diptera: Cecidomyiidae), a dominant natural enemy of aphids, has been used as a biological control agent in many countries to control aphids in greenhouses. To identify key factors that induce diapause in , we evaluated the effects of photoperiod and temperature on the incidence of diapause in under laboratory conditions. The results showed that temperature and photoperiod had significant impacts on development and diapause in Low temperatures and a short photoperiod inhibited development, while high temperatures and a long photoperiod promoted development. Temperatures above 20 °C and a photoperiod greater than 14 h prevented diapause in . However, the highest diapause rate was recorded at under 15 °C and 10L:14D photoperiod conditions. At 15 °C, the first to third larvae were sensitive to a short photoperiod at any stage, and a short photoperiod had a cumulative effect on diapause induction. The longer the larvae received short light exposure, the higher the diapause rate appeared to be. Transcriptome sequencing analysis at different stages of diapause showed that differentially expressed genes were mainly enriched in the glucose metabolism pathway. Physiological and biochemical analyses showed that diapausing reduced water content; accumulated glycogen, trehalose, sorbitol, and triglycerides; and gradually reduced trehalose and triglyceride contents in the body with the extension of diapause time. Glycogen may be used as a source of energy, but sorbitol is usually used as a cryoprotectant. This study provided results on aspects of diapause in , providing data and theoretical support for promoting its commercial breeding and in-depth research on the molecular mechanisms underlying diapause regulation.
PubMed: 38786855
DOI: 10.3390/insects15050299