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TYAPs maintain the TCA cycle and mitochondrial homeostasis to activate TET2 in the cerebral cortex. TYAPs improve diabetes-induced neuronal apoptosis through restoring the 5hmC level, which is mediated by the up-regulation and activation of TET2.

On-demand designed theranostics nanoagents show promising applications for next-generation precision-and-personalized oncotherapy. Researchers have since aimed to develop nanoplatforms that can efficiently deliver drugs and contrast medium to tumor and release active ingredients in response to tumor microenvironment (TME) conditions. Herein, we propose a modular strategy, and develop a series of nanoplatforms based on metal-coordinated-polyprodrugs for cancer theranostics. The polyprodrugs were synthesized through a click-reaction between amino acid and doxorubicin (DOX) with dipropiolate. The backbones of the polyprodrugs had intrinsic sensitivities to pH and/or GSH, and provided abundant -COOH, -NH2, or -S-S- to chelate with functional metal ions and further self-assembled to form different morphologies. Dicysteine, which contains disulfide bond (-S-S-), was chosen to copolymerize with DOX and triethylene glycol dipropiolate (TEP) to prepare the pH/GSH dual-responsive polyprodrug poly(dicysteine-co-TEP-co-DOX) (pDTD), then separately coordinated with Gd3+, Fe3+, and Mn2+ to construct nanoplatforms pDTD@M (M representing the metal ions). In vitro and in vivo investigations suggest the metal-coordinated-polyprodrug nanoplatforms have good magnetic resonance imaging (MRI) ability and efficient tumor-growth inhibition with high safety. The design strategy of nanoplatforms based on metal-coordinated-polyprodrugs provides a new idea for on-demand construction of promising theranostics agents. STATEMENT OF SIGNIFICANCE: Compared to small molecule antitumor drugs, polymeric drugs have high drug loading ratio and are easily enriched at the tumor site to achieve improved therapy efficacy. This work utilizes click reactions to link amino acids with anticancer drugs to produce polymeric drugs that are degraded in response to tumor microenvironment and released small molecule antitumor drugs mainly in tumor sites, and subtly utilizes the coordination of amino acid to chelate MRI functional metal ion to realize enhanced MRI imaging mediated tumor therapy. This strategy provides a new idea for the convenient construction of polymeric drugs for tumor theranostics.

Mitochondrion is the powerhouse of the cell. The research of nearly a century has expanded our understanding of mitochondrion, far beyond the view that mitochondrion is an important energy generator of cells. During the initiation, growth and survival of tumor cells, significant mitochondrial metabolic changes have taken place in the important enzymes of respiratory chain and tricarboxylic acid cycle, mitochondrial biogenesis and dynamics, oxidative stress regulation and molecular signaling. Therefore, mitochondrial metabolic proteins are the key mediators of tumorigenesis. Post-translational modification is the molecular switch that regulates protein function. Understanding how these mitochondria-related post-translational modification function during tumorigenesis will bring new ideas for the next generation of cancer treatment.

Mitochondria are the most important organelles in energy metabolism. Complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are formed by proteins of dual origin synthesized in the cytosol or mitochondria. The mechanisms underlying specific translation by mitoribosomes in mammals are largely unknown. Here, we report a chaperone protein of cytochrome c oxidase (COX) assembly, PET117 plays a critical role in the synthesis of mitochondrial-encoded COX1 protein in human cells. Lack of PET117 impaired mitochondrial function via suppression of mitochondrial oxygen consumption rate (OCR), probably due to reduced stability of TACO1, a COX1 translational activator. We uncovered the role of PET117 in mitochondrial regulation and a novel PET117-TACO1 axis modulating mitochondrial gene expression.

One of the beneficial effects of molecular hydrogen (H2, hydrogen gas) is neuroprotection and prevention of neurological disorders. It is important and useful if taking H2 every day can prevent or ameliorate the progression of neurodegenerative disorders, such as Parkinson’s disease or Alzheimer’s disease, both lacking specific therapeutic drugs. There are several mechanisms of how H2 protects neuronal damage. Anti-oxidative, anti-inflammatory, and the regulation of the endocrine system via stomach-brain connection seem to play an important role. At the cellular and tissue level, H2 appears to prevent the production of reactive oxygen species (ROS), and not only hydroxy radical (•OH) but also superoxide. In Parkinson’s disease model mice, chronic intake of H2 causes the release of ghrelin from the stomach. In Alzheimer’s disease model mice, sex-different neuroprotection is observed by chronic intake of H2. In female mice, declines of estrogen and estrogen receptor-β (ERβ) are prevented by H2, upregulating brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB). The question of how drinking H2 upregulates the release of ghrelin or attenuates the decline of estrogen remains to be investigated and the mechanism of how H2 modulates endocrine systems and the fundamental question of what or where is the target of H2 needs to be elucidated for a better understanding of the effects of H2.

In the last decade, breakthroughs in liquid-phase transmission electron microscopy (TEM) have enabled in situ visualization of the motion dynamics of nanostructures in liquid media with unprecedented detail. However, it remains a significant challenge to perform liquid-phase TEM due to the intricate preparation procedure of liquid cells to keep liquid from evaporating under ultrahigh vacuum conditions in TEM columns. In the present study, the nonvolatility and remarkable solvation property of ionic liquids (ILs) is exploited to image the dynamic processes of DNA supramolecular aggregates and Au nanoparticle (NP) aggregates encompassing Brownian motions, interactions among individual nanoobjects and changes in architecture at nanometer resolution. Significant differences in motion behaviors are observed between DNA supramolecular aggregates and Au NP aggregates. Moreover, the temperature and dose dependence of dynamic motions are also investigated. The findings provide insights into the dynamics of DNA supramolecular aggregates and Au NP aggregates in ILs and present an easily accessible approach for probing the dynamic processes of biomacromolecular and other soft matter aggregates with various kinds of ILs at the nanoscale level.

In addition to beta-amyloid (Aβ) plaques and neurofibrillary tangles, Alzheimer's disease (AD) is typically triggered or accompanied by abnormal inflammation, oxidative stress and astrocyte activation. Safflower (Carthamus tinctorius L.) leaf, featuring functional ingredients, is a commonly consumed leafy vegetable. Whether and how dietary safflower leaf powder (SLP) ameliorates cognitive function in an AD mouse model has remained minimally explored. Therefore, we orally administered SLP to APP/PS1 transgenic mice to explore the neuroprotective effects of SLP in preventing AD progression. We found that SLP markedly improved cognitive impairment in APP/PS1 mice, as indicated by the water maze test. We further demonstrated that SLP treatment ameliorated inflammation, oxidative stress and excessive astrocyte activation. Further investigation indicated that SLP decreased the Aβ burden in APP/PS1 mice by mediating excessive astrocyte activation. Our study suggests that safflower leaf is possibly a promising, cognitively beneficial food for preventing and alleviating AD-related dementia.

Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.

Significance Precise and efficient coupling of endocytosis to exocytosis is critical for neurotransmission. The activity-dependent facilitation of endocytosis has been well established for efficient membrane retrieval; however, whether neural activity clamps endocytosis to avoid excessive membrane retrieval remains debatable with the mechanisms largely unknown. The present work provides compelling evidence that synaptotagmin-1 (Syt1) functions as a primary bidirectional Ca 2+ sensor to promote slow, small-sized clathrin-mediated endocytosis but inhibit the fast, large-sized bulk endocytosis during elevated neural activity, the disruption of which leads to inefficient vesicle recycling under mild stimulation but excessive membrane retrieval following sustained neurotransmission. Thus, Syt1 serves as a fine-tuning Ca 2+ sensor to ensure both efficient and precise coupling of endocytosis to exocytosis in response to different neural activities.

MYC drives the tumorigenesis of human cancers, including prostate cancer (PrCa), thus deubiquitinase (DUB) that maintains high level of c-Myc oncoprotein is a rational therapeutic target. Several ubiquitin-specific protease (USP) family members of DUB have been reported to deubiquitinate c-Myc, but none of them is the physiological DUB for c-Myc in PrCa. By screening all the DUBs, here we reveal that OTUD6A is exclusively amplified and overexpressed in PrCa but not in other cancers, eliciting a prostatic-specific oncogenic role through deubiquitinating and stabilizing c-Myc oncoprotein. Moreover, genetic ablation of OTUD6A efficiently represses prostatic tumorigenesis of both human PrCa cells and the Hi-Myc transgenic PrCa mice, via reversing the metabolic remodeling caused by c-Myc overexpression in PrCa. These results indicate that OTUD6A is a physiological DUB for c-Myc in PrCa setting and specifically promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein, suggesting that OTUD6A could be a unique therapeutic target for Myc-driven PrCa.

Cellular hydrostatic pressure beyond its normal range can induce the accumulation of reactive oxidative species (ROS) generated by mitochondria and lead to pathological conditions such as glaucomatous optic neuropathy. However, little is known about how the mitochondrial electron transfer chain (ETC) is affected by elevated pressure. Moreover, the protective effects of hydrogen on various pathological conditions have been observed by reductions in ROS, yet the role of hydrogen in high hydrostatic pressure (HHP)-induced cell damage remains obscure. The goal of this study was to investigate the effect of HHP on ETC activity and whether hydrogen exerts protective effects against HHP-induced damage in cultured neuronal cells. Cultured SH-SY5Y human neuroblastoma cells were exposed to an elevated ambient hydrostatic pressure of 50 mmHg for a period of 2 to 6 h. HHP impaired the activities of ETC complexes, and these effects were reversed by hydrogen. Significant increases in apoptotic rates and intracellular ROS levels were observed in HHP-treated SH-SY5Y cells. Hydrogen significantly inhibited the apoptotic rates and reduced the levels of ROS. These findings suggest that HHP induces cell damage by causing ETC dysfunction to increase oxidative stress and that hydrogen may act as a protective agent to alleviate HHP-induced neuronal injury.

Mitochondrial epigenetics is rising as intriguing notion for its potential involvement in aging and diseases, while the details remain largely unexplored. Here it is shown that among the 13 mitochondrial DNA (mtDNA) encoded genes, NADH‐dehydrogenase 6 (ND6) transcript is primarily decreased in obese and type 2 diabetes populations, which negatively correlates with its distinctive hypermethylation. Hepatic mtDNA sequencing in mice unveils that ND6 presents the highest methylation level, which dramatically increases under diabetic condition due to enhanced mitochondrial translocation of DNA methyltransferase 1 (DNMT1) promoted by free fatty acid through adenosine 5’‐monophosphate (AMP)‐activated protein kinase (AMPK) activation. Hepatic knockdown of ND6 or overexpression of Dnmt1 similarly impairs mitochondrial function and induces systemic insulin resistance both in vivo and in vitro. Genetic or chemical targeting hepatic DNMT1 shows significant benefits against insulin resistance associated metabolic disorders. These findings highlight the pivotal role of ND6 epigenetic network in regulating mitochondrial function and onset of insulin resistance, shedding light on potential preventive and therapeutic strategies of insulin resistance and related metabolic disorders from a perspective of mitochondrial epigenetics., Metabolic disorders emerge as one of the biggest public health challenges with distinctive feature of elevated free fatty acid, which can promote mitochondrial translocation of DNA methyltransferase 1 in liver, resulting in hypermethylation of NADHdehydrogenase 6 (ND6) on mitochondrial DNA. Such molecular change suppresses ND6 expression and induces hepatic mitochondrial dysfunction, eventually provokes systemic insulin resistance.

Sleep deprivation has profound influence on several aspects of health and disease. Mitochondria dysfunction has been implicated to play an essential role in the neuronal cellular damage induced by sleep deprivation, but little is known about how neuronal mitochondrial ultrastructure is affected under sleep deprivation. In this report, we utilized electron cryo-tomography to reconstruct the three-dimensional (3-D) mitochondrial structure and extracted morphometric parameters to quantitatively characterize its reorganizations. Isolated mitochondria from the hippocampus and cerebral cortex of adult male Sprague–Dawley rats after 72 h of paradoxical sleep deprivation (PSD) were reconstructed and analyzed. Statistical analysis of six morphometric parameters specific to the mitochondrial inner membrane topology revealed identical pattern of changes in both the hippocampus and cerebral cortex but with higher significance levels in the hippocampus. The structural differences were indistinguishable by conventional phenotypic methods based on two-dimensional electron microscopy images or 3-D electron tomography reconstructions. Furthermore, to correlate structure alterations with mitochondrial functions, high-resolution respirometry was employed to investigate the effects of PSD on mitochondrial respiration, which showed that PSD significantly suppressed the mitochondrial respiratory capacity of the hippocampus, whereas the isolated mitochondria from the cerebral cortex were less affected. These results demonstrate the capability of the morphometric parameters for quantifying complex structural reorganizations and suggest a correlation between PSD and inner membrane architecture/respiratory functions of the brain mitochondria with variable effects in different brain regions.

Background Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe acute respiratory syndrome, has resulted in a global outbreak. Objective To systematically review the therapeutic reports on COVID-19 treated with integrated herbal medicine “Lianhua-Qingwen”and Western medicine to evaluate the efficacy and safety of the treatment. Methods PubMed, Embase, Web of Science, CNKI, CBM and other databases were searched to locate the clinical trials of integrated Lianhua-Qingwen and Western medicine treatment for COVID-19. The herbal medicine Lianhua-Qingwen reported in the treatments is in the form of capsules or granules. Two researchers of our team independently carried out data extraction and quality assessment of the collected literature according to the Cochrane systematic review methodology, calculated combined relative risk (RR) or weighted mean difference (MD)/standardized mean difference (SMD) . Results This meta-analysis included 13 studies collected, a total of 1182 cases of patients with common type COVID-19. Comparison of integrated Lianhua-Qingwen and Western medicine treatment with conventional Western medicine treatment found that the effective combined RR value was 1.18 (95% CI: 1.09, 1.27; I2 = 37%), and the RR value of CT image improvement rate was 1.12 (95% CI: 1.03, 1.23; I2 = 38%). The rate of progressing to critical cases decreased by 50% (RR: 0.50; 95% CI: 0.35, 0.73; I2 = 0%); the RR value of the fever disappearance rate was 1.43 (95% CI: 1.24, 1.65; I2 = 0%); the RR value of the cough disappearance rate was 1.97 (95% CI: 1.45, 2.68; I2 = 0%); the RR value of the rate of recovery from fatigue was 1.51 (95% CI: 1.15, 2.03; I2 = 0%). Compared with conventional Western medicine treatment, the integrated therapy shortened the duration of fever by 1.33 days (95% CI: -1.92, -0.73; I2 = 5%). The number of adverse reactions decreased by 49% (RR = 0.51; 95% CI: 0.14, 1.82; I2 = 76%). Conclusion Therapy of integrated Lianhua-Qingwen and Western medicine treatment is more effective for the treatment of patients with common type COVID-19, more effective in CT improvement rate, and more effective in reducing the rate of progressing to critical cases significantly and with fewer adverse reactions.

Dietary restriction has been well-described to improve health metrics, but whether it could benefit pathophysiological adaptation to extreme environment, for example, microgravity, remains unknown. Here, we investigated the effects of a daily rhythm of fasting and feeding without reducing caloric intake on cardiac function and metabolism against simulated microgravity. Male rats under ad libitum feeding or time-restricted feeding (TRF; food access limited to 8 hours every day) were subjected to hindlimb unloading (HU) to simulate microgravity. HU for 6 weeks led to left ventricular dyssynchrony and declined cardiac function. HU also lowered pyruvate dehydrogenase (PDH) activity and impaired glucose utilization in the heart. All these were largely preserved by TRF. TRF showed no effects on HU-induced loss of cardiac mass, but significantly improved contractile function of cardiomyocytes. Interestingly, TRF raised liver-derived fibroblast growth factor 21 (FGF21) level and enhanced cardiac FGF21 signaling as manifested by upregulation of FGF receptor-1 (FGFR1) expression and its downstream markers in HU rats. In isolated cardiomyocytes, FGF21 treatment improved PDH activity and glucose utilization, consequently enhancing cell contractile function. Finally, both liver-specific knockdown (KD) of FGF21 and cardiac-specific FGFR1 KD abrogated the cardioprotective effects of TRF in HU rats. These data demonstrate that TRF improves cardiac glucose utilization and ameliorates cardiac dysfunction induced by simulated microgravity, at least partially, through restoring cardiac FGF21 signaling, suggesting TRF as a potential countermeasure for cardioprotection in long-term spaceflight.

Significance: Epidemiological studies indicate that metabolic disorders are associated with an increased risk for Alzheimer's disease (AD). Metabolic remodeling occurs in the central nervous system (CNS) and periphery, even in the early stages of AD. Mitochondrial dysfunction has been widely accepted as a molecular mechanism underlying metabolic disorders. Therefore, focusing on early metabolic changes, especially from the perspective of mitochondria, could be of interest for early AD diagnosis and intervention. Recent Advances: We and others have identified that the levels of several metabolites are fluctuated in the periphery before their accumulation in the CNS, which plays an important role in the pathogenesis of AD. Mitochondrial remodeling is likely one of the earliest signs of AD, linking nutritional imbalance to cognitive deficits. Notably, by improving mitochondrial function, mitochondrial nutrients efficiently rescue cellular metabolic dysfunction in the CNS and periphery in individuals with AD. Critical Issues: Peripheral metabolic disorders should be intensively explored and evaluated for the early diagnosis of AD. The circulating metabolites derived from mitochondrial remodeling represent novel potential diagnostic biomarkers for AD that are more readily detected than CNS-oriented biomarkers. Moreover, mitochondrial nutrients provide a promising approach to preventing and delaying AD progression. Future Directions: Abnormal mitochondrial metabolism in the CNS and periphery is involved in AD pathogenesis. More clinical studies provide evidence for the suitability and reliability of circulating metabolites and cytokines for the early diagnosis of AD. Targeting mitochondria to rewire cellular metabolism is a promising approach to preventing AD and ameliorating AD-related metabolic disorders.

Combining doxorubicin with thermal therapy in the clinic has led to startling results in the treatment of problematic cancers. Here, we describe a multimo dal multi-walled carbon nanotube material that combines tumor targeting, doxorubicin delivery, and photothermal therapy for localized cancer treatment. The agent was constructed layer-by-layer from polypyrrole and gold nanoparticles on multi-walled carbon nanotubes. The gold surface was modified with tumor targeting folic acid terminated PEGylated chains, which also provide water-dispersibility, biocompatibility and should extend the half-life in blood. The material has a high loading/unloading capacity for the cytotoxic agent doxorubicin. Release of the doxorubicin, combined with the photothermal properties of the material that induces localized hyperthermia, leads to efficient cancer cell death.

Alzheimer's disease (AD) is characterised as a provoked inflammatory response and oxidative stress along with amyloid β peptide (Aβ) deposition and neurofibrillary tangles in the brain, and effective treatment is greatly needed. Molecular hydrogen, which has been proposed to be an antioxidant that selectively reduces reactive oxygen species, was found to exert beneficial effects in Aβ injection-induced cognitive dysfunction. However, whether and how hydrogen affects AD pathogenesis remains uninvestigated. Thus, in the present study, APPswe/PS1dE9 (amyloid precursor protein (APP)/PS1) mice, a transgenic AD mouse model, were administered hydrogen-rich water for 3 months and the effects on cognitive function and molecular pathways were investigated. We found that hydrogen-rich water significantly improved cognitive behaviour in female transgenic AD mice without affecting Aβ clearance, and reversed the brain oestrogen level, ERβ, and brain-derived neurotrophic factor (BDNF) expressions that were damaged in female transgenic AD mice, but not in males. Furthermore, hydrogen-rich water ameliorated oxidative stress and inflammatory responses more profoundly in the brains of female AD mice than in those of males. Our results demonstrate a novel sex-specific beneficial effect of hydrogen via oestrogen and brain ERβ-BDNF signalling in AD pathogenesis.

The multipurpose organelle mitochondria play an essential role(s) in controlling cardiac muscle contraction. Mitochondria, not only function as the powerhouses and the energy source of myocytes but also modulate intracellular Ca2+ homeostasis, the production of intermediary metabolites/reactive oxygen species (ROS), and other cellular processes. Those molecular events can substantially influence myocardial contraction. Mitochondrial dysfunction is usually associated with cardiac remodelling, and is the causal factor of heart contraction defects in many cases. The manipulation of mitochondria or mitochondria-relevant pathways appears to be a promising therapeutic approach to treat the diseases.

Recent studies have revealed robust metabolic changes during cell differentiation. Mitochondria, the organelles where many vital metabolic reactions occur, may play an important role. Here, we report the involvement of SIRT3-regulated mitochondrial stress in osteoblast differentiation and bone formation. In both the osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts, robust mitochondrial biogenesis and supercomplex formation were observed during differentiation, accompanied by increased ATP production and decreased mitochondrial stress. Inhibition of mitochondrial activity or an increase in mitochondrial superoxide production significantly suppressed osteoblast differentiation. During differentiation, SOD2 was specifically induced to eliminate excess mitochondrial superoxide and protein oxidation, whereas SIRT3 expression was increased to enhance SOD2 activity through deacetylation of K68. Both SOD2 and SIRT3 knockdown resulted in suppression of differentiation. Meanwhile, mice deficient in SIRT3 exhibited obvious osteopenia accompanied by osteoblast dysfunction, whereas overexpression of SOD2 or SIRT3 improved the differentiation capability of primary osteoblasts derived from SIRT3-deficient mice. These results suggest that SIRT3/SOD2 is required for regulating mitochondrial stress and plays a vital role in osteoblast differentiation and bone formation.

Alzheimer's disease (AD) is considered a multifactorial disease that affects the central nervous system and periphery. A decline in brain glucose metabolism is an early feature of AD and is accompanied by a phenotypic shift from aerobic glycolysis to ketogenesis. The liver is responsible for the generation of the ketone body. However, the mechanism that underlies hepatic ketogenesis in AD remains unclear. Here, we investigated hepatic ketogenesis during the early stage of AD pathogenesis in amyloid precursor protein (APPSWE) and presenilin (PSEN1dE9) (APP/PS1) mice. We observed that β-hydroxybutyric acid was increased in the brain of the postmortem mild cognitive impairment and AD subjects and in 3-month-old APP/PS1 AD mice. A rise in 3-hydroxy-3-methylglutary-CoA synthase 2 (HMGCS2), a key enzyme for catalyzing β-hydroxybutyric acid production, was observed in early AD mice. We further showed that proinflammatory cytokines were activated in the liver prior to their activation in the brain of 3-month-old APP/PS1 mice. Among the cytokines, interleukin-6 significantly activated HMGCS2 through the binding of nuclear factor κB (NF-κB) p65 to the HMGCS2 promoter. Additionally, interleukin-6 stimulated phosphorylation of p38 mitogen activated protein kinases, an upstream molecule for NF-κB p65 signaling. We have demonstrated that a hepatic inflammatory factor enhances ketogenesis through HMGCS2 signaling activation by p38/NF-κB p65. These results provide a novel peripheral metabolic mechanism for enhanced ketone production and suggest a plausible early AD phenotype to diagnose AD.

Cullin (CUL) proteins have critical roles in development and cancer, however few studies on CUL7 have been reported due to its characteristic molecular structure. CUL7 forms a complex with the ROC1 ring finger protein, and only two F-box proteins Fbxw8 and Fbxw11 have been shown to bind to CUL7. Interestingly, CUL7 can interact with its substrates by forming a novel complex that is independent of these two F-box proteins. The biological implications of CUL-ring ligase 7 (CRL7) suggest that the CRL7 may not only perform a proteolytic function but may also play a non-proteolytic role. Among the existing studied CRL7-based E3 ligases, CUL7 exerts both tumor promotion and suppression in a context-dependent manner. Currently, the mechanism of CUL7 in cancer remains unclear, and no studies have addressed potential therapies targeting CUL7. Consistent with the roles of the various CRL7 adaptors exhibit, targeting CRL7 might be an effective strategy for cancer prevention and treatment. We systematically describe the recent major advances in understanding the role of the CUL7 E3 ligase in cancer and further summarize its potential use in clinical therapy.

SKP1-cullin-1-F-box-protein (SCF) E3 ubiquitin ligase complex is responsible for the degradation of proteins in a strictly regulated manner, through which it exerts pivotal roles in regulating various key cellular processes including cell cycle and division, apoptosis, and differentiation. The substrate specificity of the SCF complex largely depends on the distinct F-box proteins, which function in either tumor promotion or suppression or in a context-dependent manner. Among the 69 F-box proteins identified in human genome, FBW7, SKP2, and β-TRCP have been extensively investigated among various types of cancer in respective of their roles in cancer development, progression, and metastasis. Moreover, several specific inhibitors have been developed to target those E3 ligases, and their efficiency in tumors has been determined. In this review, we provide a summary of the roles of SCF E3 ligases in cancer development, as well as the potential application of miRNA or specific inhibitors for cancer therapy.

SKP1-cullin-1-F-box-protein (SCF) E3 ubiquitin ligase complex is responsible for the degradation of proteins in a strictly regulated manner, through which it exerts pivotal roles in regulating various key cellular processes including cell cycle and division, apoptosis, and differentiation. The substrate specificity of the SCF complex largely depends on the distinct F-box proteins, which function in either tumor promotion or suppression or in a context-dependent manner. Among the 69 F-box proteins identified in human genome, FBW7, SKP2, and β-TRCP have been extensively investigated among various types of cancer in respective of their roles in cancer development, progression, and metastasis. Moreover, several specific inhibitors have been developed to target those E3 ligases, and their efficiency in tumors has been determined. In this review, we provide a summary of the roles of SCF E3 ligases in cancer development, as well as the potential application of miRNA or specific inhibitors for cancer therapy.