Expression profiling of ALOG family genes during inflorescence development and abiotic stress responses in rice (Oryza sativa L.).

The ALOG (Arabidopsis LSH1 and Oryza G1) family proteins, namely, DUF640 domain-containing proteins, have been reported to function as transcription factors in various plants. However, the understanding of the response and function of ALOG family genes during reproductive development and under abiotic stress is still largely limited. In this study, we comprehensively analyzed the structural characteristics of ALOG family proteins and their expression profiles during inflorescence development and under abiotic stress in rice. The results showed that OsG1/OsG1L1/2/3/4/5/6/7/8/9 all had four conserved helical structures and an inserted Zinc-Ribbon (ZnR), the other four proteins OsG1L10/11/12/13 lacked complete Helix-1 and Helix-2. In the ALOG gene promoters, there were abundant cis-acting elements, including ABA, MeJA, and drought-responsive elements. Most ALOG genes show a decrease in expression levels within 24 h under ABA and drought treatments, while OsG1L2 expression levels show an upregulated trend under ABA and drought treatments. The expression analysis at different stages of inflorescence development indicated that OsG1L1/2/3/8/11 were mainly expressed in the P1 stage; in the P4 stage, OsG1/OsG1L4/5/9/12 had a higher expression level. These results lay a good foundation for further studying the expression of rice ALOG family genes under abiotic stresses, and provide important experimental support for their functional research.

A robust high-throughput functional screening assay for plant pathogen effectors using the TMV-GFP vector.

Uncovering the function of phytopathogen effectors is crucial for understanding mechanisms of pathogen pathogenicity and for improving our ability to protect plants from diseases. An increasing number of effectors have been predicted in various plant pathogens. Functional characterization of these effectors has become a major focus in the study of plant-pathogen interactions. In this study, we designed a novel screening system that combines the TMV (tobacco mosaic virus)-GFP vector and Agrobacterium-mediated transient expression in the model plant Nicotiana benthamiana. This system enables the rapid identification of effectors that interfere with plant immunity. The biological function of these effectors can be easily evaluated by observing the GFP fluorescence signal using a UV lamp within just a few days. To evaluate the TMV-GFP system, we initially tested it with well-described virulence and avirulence type III effectors from the bacterial pathogen Ralstonia solanacearum. After proving the accuracy and efficiency of the TMV-GFP system, we successfully screened a novel virulence effector, RipS1, using this approach. Furthermore, using the TMV-GFP system, we reproduced consistent results with previously known cytoplasmic effectors from a diverse array of pathogens. Additionally, we demonstrated the effectiveness of the TMV-GFP system in identifying apoplastic effectors. The easy operation, time-saving nature, broad effectiveness, and low technical requirements of the TMV-GFP system make it a promising approach for high-throughput screening of effectors with immune interference activity from various pathogens.

Rastonia solanacearum type â ¢ effectors target host 14-3-3 proteins to suppress plant immunity.

14-3-3 proteins play important roles in plant metabolism and stress response. Tomato 14-3-3 proteins, SlTFT4 and SlTFT7, serve as hubs of plant immunity and are targeted by some pathogen effectors. Ralstonia solanacearum with more than 70 type Ⅲ effectors (T3Es) is one of the most destructive plant pathogens. However, little is known on whether R. solanacearum T3Es target SlTFT4 and SlTFT7 and hence interfere with plant immunity. We first detected the associations of SlTFT4/SlTFT7 with R. solanacearum T3Es by luciferase complementation assay, and then confirmed the interactions by yeast two-hybrid approach. We demonstrated that 22 Ralstonia T3Es were associated with both SlTFT4 and SlTFT7, and five among them suppressed the hypersensitive response induced by MAPKKKα, a protein kinase which associated with SlTFT4/SlTFT7. We further demonstrated that suppression of MAPKKKα-induced HR and plant basal defense by the T3E RipAC depend on its association with 14-3-3 proteins. Our findings firstly demonstrate that R. solanacearum T3Es can manipulate plant immunity by targeting 14-3-3 proteins, SlTFT4 and SlTFT7, providing new insights into plant-R. solanacearum interactions.

Effects of Aegilops longissima chromosome 1Sl on wheat bread-making quality in two types of translocation lines.

KEY MESSAGE: Two wheat-Ae. longissima translocation chromosomes (1BS·1SlL and 1SlS·1BL) were transferred into three commercial wheat varieties, and the new advanced lines showed improved bread-making quality compared to their recurrent parents. Aegilops longissima chromosome 1Sl encodes specific types of gluten subunits that may positively affect wheat bread-making quality. The most effective method of introducing 1Sl chromosomal fragments containing the target genes into wheat is chromosome translocation. Here, a wheat-Ae. longissima 1BS·1SlL translocation line was developed using molecular marker-assisted chromosome engineering. Two types of translocation chromosomes developed in a previous study, 1BS·1SlL and 1SlS·1BL, were introduced into three commercial wheat varieties (Ningchun4, Ningchun50, and Westonia) via backcrossing with marker-assisted selection. Advanced translocation lines were confirmed through chromosome in situ hybridization and genotyping by target sequencing using the wheat 40 K system. Bread-making quality was found to be improved in the two types of advanced translocation lines compared to the corresponding recurrent parents. Furthermore, 1SlS·1BL translocation lines displayed better bread-making quality than 1BS·1SlL translocation lines in each genetic background. Further analysis revealed that high molecular weight glutenin subunit (HMW-GS) contents and expression levels of genes encoding low molecular weight glutenin subunits (LMW-GSs) were increased in 1SlS·1BL translocation lines. Gliadin and gluten-related transcription factors were also upregulated in the grains of the two types of advanced translocation lines compared to the recurrent parents. This study clarifies the impacts of specific glutenin subunits on bread-making quality and provides novel germplasm resources for further improvement of wheat quality through molecular breeding.

Heat shock protein TaHSP17.4, a TaHOP interactor in wheat, improves plant stress tolerance.

Adaptation to drought and salt stresses is a fundamental part of plant cell physiology and is of great significance for crop production under environmental stress. Heat shock proteins (HSPs) are molecular chaperones that play a crucial role in folding, assembling, translocating, and degrading proteins. However, their underlying mechanisms and functions in stress tolerance remain elusive. Here, we identified the HSP TaHSP17.4 in wheat by analyzing the heat stress-induced transcriptome. Further analysis showed that TaHSP17.4 was significantly induced under drought, salt, and heat stress treatments. Intriguingly, yeast-two-hybrid analysis showed that TaHSP17.4 interacts with the HSP70/HSP90 organizing protein (HOP) TaHOP, which plays a significant role in linking HSP70 and HSP90. We found that TaHSP17.4- and TaHOP-overexpressing plants have a higher proline content and a lower malondialdehyde content than wild-type plants under stress conditions and display strong tolerance to drought, salt, and heat stress. Additionally, qRT-PCR analysis showed that stress-responsive genes relevant to reactive oxygen species scavenging and abscisic acid signaling pathways were significantly induced in TaHSP17.4- and TaHOP-overexpressing plants under stress conditions. Together, our findings provide insight into HSP functions in wheat and two novel candidate genes for improvement of wheat varieties.

Thinned young apple polyphenols may prevent neuronal apoptosis by up-regulating 5-hydroxymethylcytosine in the cerebral cortex of high-fat diet-induced diabetic mice.

Apple polyphenols exert neuroprotective effects by improving the mitochondrial tricarboxylic acid (TCA) cycle function, but the details of their mechanisms are still not fully understood. TCA cycle metabolites regulate the level of 5-hydroxymethylcytosine (5hmC) by affecting the ten-eleven translocation (TET) enzyme activity. Therefore, we hypothesized that thinned young apple polyphenols (TYAPs) inhibit neuronal apoptosis by up-regulating the level of 5hmC in the cerebral cortex of high-fat diet-induced diabetic mice. C57BL/6J mice were randomly divided into 5 groups (n = 10 each group): the control (CON) group, the high-fat diet (HFD, negative control) group, the lovastatin (LOV, positive drug control) group, the resveratrol (RES, positive polyphenol control) group and the TYAP group during an eight-week intervention. The presented results verified that in the HFD group, the level of 5hmC and the expression of TET2 in the cerebral cortex were significantly lower, and the ratio of (succinic acid + fumaric acid)/α-ketoglutarate and the neuronal apoptosis rate were significantly higher than those in the CON group. However, TYAP intervention effectively restored the level of 5hmC through up-regulating the expression and activity of TET2, so as to improve diabetes symptoms and prevent diabetes-induced neuronal apoptosis.

Immune checkpoint inhibitors for patients with microsatellite instability-high colorectal cancer: protocol of a pooled analysis of clinical trials.

Introduction: Colorectal cancer (CRC) is the third most common cause of cancer and the second leading cause of cancer-related deaths worldwide. Microsatellite instability-high (MSI-H) is a distinct molecular subtype of CRC that occurs in approximately 15% of all cases. Recently, immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic approach for patients with MSI-H colorectal cancer, exhibiting higher response rates than standard chemotherapies. To assess the effectiveness and safety of ICIs for the treatment of patients with MSI-H CRC, we propose a comprehensive pooled analysis of clinical trial data. Methods and analysis: A systematic search of multiple electronic databases, including PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov, will be conducted from their inception until September, 2023 to identify eligible randomized controlled trials (RCTs) and non-randomized studies. Inclusion criteria comprise studies of adult patients with histologically confirmed MSI-H CRC treated with immune checkpoint inhibitors, with a comparison to a control group receiving conventional therapies. Outcomes of interest will be overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and incidence of treatment-related adverse events (AEs). The Cochrane Risk of Bias tool and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool will be employed to evaluate the methodological quality of included studies. A random-effects model using the DerSimonian and Laird method will be applied for pooling the effect estimates, calculating hazard ratios (HRs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs). Heterogeneity will be assessed using I² statistics, and subgroup analysis and meta-regression will be performed to explore potential effect modifiers in case of substantial heterogeneity. Publication bias will be evaluated with funnel plots and Egger's test. Sensitivity analysis will be conducted to assess the robustness of the results. Discussion: This meta-analysis will synthesize available evidence from clinical trials on immune checkpoint inhibitors in treating MSI-H colorectal cancer. The findings will offer valuable information about the effectiveness and safety of ICIs in this patient population, contributing to the refinement of clinical guidelines and enhancing the decision-making process for healthcare providers, policy-makers, and patients. The comprehensive analysis of subgroups and sensitivity allows for an in-depth understanding of potential effect modification, providing essential directions for future research. Ethics and dissemination: This study will involve the use of published data; hence, ethical approval is not required. The results of the study will be disseminated through publications in peer-reviewed journals and presentations at relevant conferences. The findings will potentially impact clinical decision-making and contribute to the development of evidence-based treatment recommendations for patients with MSI-H colorectal cancer. Clinical trial registration: Open Science Framework identifier, 10.17605/OSF.IO/ZHJ85.

The Ralstonia solanacearum Type III Effector RipAW Targets the Immune Receptor Complex to Suppress PAMP-Triggered Immunity.

Bacterial wilt, caused by Ralstonia solanacearum, one of the most destructive phytopathogens, leads to significant annual crop yield losses. Type III effectors (T3Es) mainly contribute to the virulence of R. solanacearum, usually by targeting immune-related proteins. Here, we clarified the effect of a novel E3 ubiquitin ligase (NEL) T3E, RipAW, from R. solanacearum on pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and further explored its action mechanism. In the susceptible host Arabidopsis thaliana, we monitored the expression of PTI marker genes, flg22-induced ROS burst, and callose deposition in RipAW- and RipAWC177A-transgenic plants. Our results demonstrated that RipAW suppressed host PTI in an NEL-dependent manner. By Split-Luciferase Complementation, Bimolecular Fluorescent Complimentary, and Co-Immunoprecipitation assays, we further showed that RipAW associated with three crucial components of the immune receptor complex, namely FLS2, XLG2, and BIK1. Furthermore, RipAW elevated the ubiquitination levels of FLS2, XLG2, and BIK1, accelerating their degradation via the 26S proteasome pathway. Additionally, co-expression of FLS2, XLG2, or BIK1 with RipAW partially but significantly restored the RipAW-suppressed ROS burst, confirming the involvement of the immune receptor complex in RipAW-regulated PTI. Overall, our results indicate that RipAW impairs host PTI by disrupting the immune receptor complex. Our findings provide new insights into the virulence mechanism of R. solanacearum.

A conserved type III effector RipB is recognized in tobacco and contributes to Ralstonia solanacearum virulence in susceptible host plants.

Ralstonia solanacearum, the causal agent of bacterial wilt, causes devastating diseases in a wide range of plants including potato, tomato, pepper and tobacco. The pathogen delivers approximately 70 type III effectors (T3Es) into plant cells during infection. In this study, we confirmed that a T3E RipB is recognized in tobacco. We further demonstrated that RipB is conserved among R. solanacearum isolates and five different ripB alleles are all recognized in tobacco. The ripB from GMI1000 was transformed into susceptible host Arabidopsis, and a defect in root development was observed in ripB-transgenic plants. Pathogen inoculation assays showed that ripB expression promoted plant susceptibility to R. solanacearum infection, indicating that RipB contributes to pathogen virulence in Arabidopsis. Expression of ripB in roq1 mutant partially suppressed reactive oxygen species production, confirming that RipB interferes with plant basal defense. Interestingly, ripB expression promoted cytokinin-related gene expression in Arabidopsis, suggesting a role of cytokinin signaling pathway in plant-R. solanacearum interactions. Finally, RipB harbors potential 14-3-3 binding motifs, but the associations between RipB and 14-3-3 proteins were undetectable in yeast two-hybrid assay. Together, our results demonstrate that multiple ripB alleles are recognized in Nicotiana, and RipB suppresses basal defense in susceptible host to promote R. solanacearum infection.

Genome-Wide Analysis of C2H2 Zinc Finger Gene Family and Its Response to Cold and Drought Stress in Sorghum [Sorghum bicolor (L.) Moench].

C2H2 zinc finger protein (C2H2-ZFP) is one of the most important transcription factor families in higher plants. In this study, a total of 145 C2H2-ZFPs was identified in Sorghum bicolor and randomly distributed on 10 chromosomes. Based on the phylogenetic tree, these zinc finger gene family members were divided into 11 clades, and the gene structure and motif composition of SbC2H2-ZFPs in the same clade were similar. SbC2H2-ZFP members located in the same clade contained similar intron/exon and motif patterns. Thirty-three tandem duplicated SbC2H2-ZFPs and 24 pairs of segmental duplicated genes were identified. Moreover, synteny analysis showed that sorghum had more collinear regions with monocotyledonous plants such as maize and rice than did dicotyledons such as soybean and Arabidopsis. Furthermore, we used quantitative RT-PCR (qRT-PCR) to analyze the expression of C2H2-ZFPs in different organs and demonstrated that the genes responded to cold and drought. For example, Sobic.008G088842 might be activated by cold but is inhibited in drought in the stems and leaves. This work not only revealed an important expanded C2H2-ZFP gene family in Sorghum bicolor but also provides a research basis for determining the role of C2H2-ZFPs in sorghum development and abiotic stress resistance.

Daphnetin ameliorates Aß pathogenesis via STAT3/GFAP signaling in an APP/PS1 double-transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) has become a major public health problem that affects the elderly population. Therapeutic compounds with curative effects are not available due to the complex pathogenesis of AD. Daphnetin, a natural coumarin derivative and inhibitor of various kinases, has anti-inflammatory and antioxidant activities. In this study, we found that daphnetin improved spatial learning and memory in an amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mouse model of AD. Daphnetin markedly decreased the levels of amyloid-ß peptide 1-40 (Aß40) and 1-42 (Aß42) in the cerebral cortex, downregulated the expressions of enzymes involved in APP processing, e.g., beta-site APP-cleaving enzyme (BACE), nicastrin and presenilin enhancer protein 2 (PEN2). We further found the reduced serum levels of inflammatory factors, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and chemokine (C-C motif) ligand 3 (CCL3), while daphnetin increased total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels in the serum. Interestingly, daphnetin markedly decreased the expression of glial fibrillary acidic protein (GFAP) and the upstream regulatory molecule- phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in APP/PS1 mice, and mainly inhibited the phosphorylation of STAT3 at Ser727 to decrease GFAP expression evidenced in a LPS-activated glial cell model. These results suggest that daphnetin ameliorates cognitive deficits and that Aß deposition in APP/PS1 mice is mainly correlated with astrocyte activation and APP processing.

Mutation of CESA1 phosphorylation site influences pectin synthesis and methylesterification with a role in seed development.

Cell wall biogenesis is required for the production of seeds of higher plants. However, little is known about regulatory mechanisms underlying cell wall biogenesis during seed formation. Here we show a role for the phosphorylation of Arabidopsis cellulose synthase 1 (AtCESA1) in modulating pectin synthesis and methylesterification in seed coat mucilage. A phosphor-null mutant of AtCESA1 on T166 (AtCESA1T166A) was constructed and introduced into a null mutant of AtCESA1 (Atcesa1-1). The resulting transgenic lines showed a slight but significant decrease in cellulose contents in mature seeds. Defects in cellulosic ray architecture along with reduced levels of non-adherent and adherent mucilage were observed on the seeds of the AtCESA1T166A mutant. Reduced mucilage pectin synthesis was also reflected by a decrease in the level of uronic acid. Meanwhile, an increase in the degree of pectin methylesterification was also observed in the seed coat mucilage of AtCESA1T166A mutant. Change in seed development was further reflected by a delayed germination and about 50% increase in the accumulation of proanthocyanidins, which is known to bind pectin and inhibit seed germination as revealed by previous studies. Taken together, the results suggest a role of AtCESA1 phosphorylation on T166 in modulating mucilage pectin synthesis and methylesterification as well as cellulose synthesis with a role in seed development.

Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc.

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.

Exogenous Application of Low-Concentration Sugar Enhances Brassinosteroid Signaling for Skotomorphogenesis by Promoting BIN2 Degradation.

In plants, seedling growth is subtly controlled by multiple environmental factors and endogenous phytohormones. The cross-talk between sugars and brassinosteroid (BR) signaling is known to regulate plant growth; however, the molecular mechanisms that coordinate hormone-dependent growth responses with exogenous sucrose in plants are incompletely understood. Skotomorphogenesis is a plant growth stage with rapid elongation of the hypocotyls. In the present study, we found that low-concentration sugars could improve skotomorphogenesis in a manner dependent on BR biosynthesis and TOR activation. However, accumulation of BZR1 in bzr1-1D mutant plants partially rescued the defects of skotomorphogenesis induced by the TOR inhibitor AZD, and these etiolated seedlings displayed a normal phenotype like that of wild-type seedlings in response to both sucrose and non-sucrose treatments, thereby indicating that accumulated BZR1 sustained, at least partially, the sucrose-promoted growth of etiolated seedlings (skotomorphogenesis). Moreover, genetic evidence based on a phenotypic analysis of bin2-3bil1bil2 triple-mutant and gain-of-function bin2-1 mutant plant indicated that BIN2 inactivation was conducive to skotomorphogenesis in the dark. Subsequent biochemical and molecular analyses enabled us to confirm that sucrose reduced BIN2 levels via the TOR-S6K2 pathway in etiolated seedlings. Combined with a determination of the cellulose content, our results indicated that sucrose-induced BIN2 degradation led to the accumulation of BZR1 and the enhancement of cellulose synthesis, thereby promoting skotomorphogenesis, and that BIN2 is the converging node that integrates sugar and BR signaling.

Safflower leaf ameliorates cognitive impairment through moderating excessive astrocyte activation in APP/PS1 mice.

In addition to beta-amyloid (Aß) 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 Aß 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.

Integrated UPLC-MS and Network Pharmacology Approach to Explore the Active Components and the Potential Mechanism of Yiqi Huoxue Decoction for Treating Nephrotic Syndrome.

Background: Yiqi Huoxue Decoction (YQHXD) is a traditional Chinese medicine that promotes blood circulation, removes blood stasis, facilitates diuresis, and alleviates edema. It is composed of 10 herbal medicines and has extensive application in treating nephrotic syndrome (NS). However, the active components and the potential mechanism of YQHXD for treating NS remain unclear. Methods: We set up a sensitive and rapid method based on Ultra-High Performance Liquid Chromatograph-Mass (UPLC-MS) to identify the compounds in YQHXD and constituents absorbed into the blood. Disease genes were collected through GeneCards, DisGeNET, and OMIM database. Genes of compounds absorbed into blood were predicted by the TCMSP database. We constructed Disease-Drug-Ingredient-Gene (DDIG) network using Cytoscape, established a Protein-protein interaction (PPI) network using String, Gene biological process (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using DAVID. Cellular experiments were performed to validate the results of network pharmacology. Result: A total of 233 compounds in YQHXD and 50 constituents absorbed into the blood of rats were identified. The 36 core targets in the PPI network were clustered in the phosphatidylinositol 3 kinase-RAC serine/threonine-protein kinase (PI3K-AKT) and nuclear factor kappa-B (NF-κB) signaling pathways. Luteolin, Wogonin, Formononetin, and Calycosin were top-ranking components as potentially active compounds. Conclusion: The results of our studies show that YQHXD is able to enhance renal function, alleviate podocyte injury, and improve adriamycin nephrotic syndrome.

Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle.

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.