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p53 regulates multiple signaling pathways and maintains cell homeostasis under conditions of DNA damage and oxidative stress. Although USP7 has been shown to promote p53 stability via deubiquitination, the USP7-p53 activation mechanism has remained unclear. Here, we propose that DNA damage induces reactive oxygen species (ROS) production and activates ATM-CHK2, and CHK2 then phosphorylates USP7 at S168 and T231. USP7 phosphorylation is essential for its deubiquitination activity toward p53. USP7 also deubiquitinates CHK2 at K119 and K131, increasing CHK2 stability and creating a positive feedback loop between CHK2 and USP7. Compared to peri-tumor tissues, thyroid cancer and colon cancer tissues show higher CHK2 and phosphorylated USP7 (S168, T231) levels, and these levels are positively correlated. Collectively, our results uncover a phosphorylation-deubiquitination positive feedback loop involving the CHK2-USP7 axis that supports the stabilization of p53 and the maintenance of cell homeostasis.
Assuntos
Quinase do Ponto de Checagem 2 , Estresse Oxidativo , Proteína Supressora de Tumor p53 , Peptidase 7 Específica de Ubiquitina , Ubiquitinação , Quinase do Ponto de Checagem 2/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismo , Humanos , Proteína Supressora de Tumor p53/metabolismo , Fosforilação , Retroalimentação Fisiológica , Dano ao DNA , Espécies Reativas de Oxigênio/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Estabilidade Proteica , AnimaisRESUMO
Litsea coreana Levl. var. sinensis (Allen) Yang et P. H. Huang is a popular ethnic herb and beverage plant known for its high flavonoid content, which has been linked to a variety of pharmacological benefits and crucial health-promoting impacts in humans. The progress in understanding the molecular mechanisms of flavonoid accumulation in this plant has been hindered due to the deficiency of genomic and transcriptomic resources. We utilized a combination of Illumina and Oxford Nanopore Technology (ONT) sequencing to generate a de novo hybrid transcriptome assembly. In total, 126,977 unigenes were characterized, out of which 107,977 were successfully annotated in seven public databases. Within the annotated unigenes, 3,781 were categorized into 58 transcription factor families. Furthermore, we investigated the presence of four valuable flavonoids-quercetin-3-O-ß-D-galactoside, quercetin-3-O-ß-D-glucoside, kaempferol-3-O-ß-D-galactoside, and kaempferol-3-O-ß-D-glucoside in 98 samples, using high-performance liquid chromatography. A weighted gene co-expression network analysis identified two co-expression modules, MEpink and MEturquoise, that showed strong positive correlation with flavonoid content. Within these modules, four transcription factor genes (R2R3-MYB, NAC, WD40, and ARF) and four key enzyme-encoding genes (CHI, F3H, PAL, and C4H) emerged as potential hub genes. Among them, the R2R3-MYB (LcsMYB123) as a homologous gene to AtMYB123/TT2, was speculated to play a significant role in flavonol biosynthesis based on phylogenetic analysis. Our findings provided a theoretical foundation for further research into the molecular mechanisms of flavonoid biosynthesis. Additionally, The hybrid transcriptome sequences will serve as a valuable molecular resource for the transcriptional annotation of L. coreana var. sinensis, which will contribute to the improvement of high-flavonoid materials.
Assuntos
Litsea , Transcriptoma , Humanos , Litsea/genética , Litsea/metabolismo , Quercetina , Filogenia , Perfilação da Expressão Gênica , Flavonoides/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
Bursaphelenchus xylophilus (Steiner&Buhrer) Nickle is a global quarantine pest that causes devastating mortality in pine species. The rapid and uncontrollable parasitic spread of this organism results in substantial economic losses to pine forests annually. In this study, we used the MaxEnt model and GIS software ArcGIS10.8 to predict the distribution of B. xylophilus based on collected distribution points and 19 environmental variables (with a correlation coefficient of|R| > 0.8) for the contemporary period (1970-2000), 2041-2060 (2050s), 2061-2080 (2070s), and 2081-2100 (2090s) under four shared socioeconomic pathways (SSPs). We conducted a comprehensive analysis of the key environmental factors affecting the geographical distribution of B. xylophilus and suitable distribution areas. Our results indicate that in current prediction maps B. xylophilus had potential suitable habitats in all continents except Antarctica, with East Asia being the region with the most highly suitable areas and the most serious epidemic area currently. Precipitation of the warmest quarter, temperature seasonality, precipitation of the wettest month, and maximum temperature of the warmest month were identified as key environmental variables that determine the distribution of B. xylophilus. Under future climatic conditions, the potential geographic distribution of B. xylophilus will expand relative to current conditions. In particular, under the SSP5-8.5 scenario in 2081-2100, suitable areas will expand to higher latitudes, and there will be significant changes in suitable areas in Europe, East Asia, and North America. These findings are crucial for future prevention and control management and monitoring.
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Pinus , Xylophilus , Ecossistema , Florestas , Temperatura , Ásia Oriental , Pinus/parasitologiaRESUMO
Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (Chk2), vital effector kinases in the DNA damage response (DDR) signaling pathway. We further demonstrate that Chk2 phosphorylates PKM2 at the T95 and T195 sites, promoting glycolysis and facilitating macrophage M1 polarization. In addition, Chk2 activation increases the Chk2-dependent expression of p21, inducing cell cycle arrest for subsequent macrophage M1 polarization. Finally, Chk2-deficient mice infected with lipopolysaccharides (LPS) display a significant decrease in lung inflammation and M1 macrophage counts. Taken together, these results suggest that inhibiting the ROS-Chk2 axis can prevent the excessive inflammatory activation of macrophages, and this pathway can be targeted to develop a novel therapy for inflammation-associated diseases and expand our understanding of the pathophysiological functions of DDR in innate immunity.
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Ataxia Telangiectasia , Proteínas Serina-Treonina Quinases , Animais , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Fosforilação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ligação a DNA/genética , Ciclo Celular , Macrófagos/metabolismo , InflamaçãoRESUMO
Several studies have demonstrated the role of the oncogenic mutant p53 in promoting tumor progression; however, there is limited information on the effects of secreted oncogenic mutant p53 on the tumor microenvironment and tumor immune escape. In this study, we found that secretion of mutant p53, determined by exosome content, is dependent on its N-terminal dileucine motif via its binding to ß-adaptin, and inhibited by the CHK2-mediated-Ser 20 phosphorylation. Moreover, we observed that the mutant p53 caused downregulation and dysfunction of CD4+ T lymphocytes in vivo and downregulated the levels and activities of rate-limiting glycolytic enzymes in vitro. Furthermore, inhibition of mutant p53 secretion by knocking down AP1B1 or mutation of dileucine motif could reverse the quantity and function of CD4+ T lymphocytes and restrain the tumor growth. Our study demonstrates that the tumor-derived exosome-mediated secretion of oncogenic mutant p53 inhibits glycolysis to alter the immune microenvironment via functional suppression of CD4+ T cells, which may be the underlying mechanism for tumor immune escape. Therefore, targeting TDE-mediated p53 secretion may serve as a potential therapeutic target for cancer treatment.
Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Microambiente Tumoral/genética , Linfócitos T/metabolismo , Mutação , Neoplasias/genética , Linhagem Celular Tumoral , Complexo 1 de Proteínas Adaptadoras/genética , Complexo 1 de Proteínas Adaptadoras/metabolismo , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/metabolismoRESUMO
Oxidative stress-induced autophagy helps to prevent cellular damage and to maintain homeostasis. However, the regulatory pathway that initiates autophagy remains unclear. We previously showed that reactive oxygen species (ROS) function as signaling molecules to activate the ATM-CHK2 pathway and promote autophagy. Here, we find that the E3 ubiquitin ligase TRIM32 functions downstream of ATM-CHK2 to regulate ATG7 ubiquitination. Under metabolic stress, ROS induce ATM phosphorylation at S1981, which in turn phosphorylates CHK2 at T68. We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy. In addition, Chk2-/- mice show an aggravated infarction phenotype and reduced phosphorylation of TRIM32 and ubiquitination of ATG7 in a stroke model. We propose a molecular mechanism for autophagy initiation by ROS via the ATM-CHK2-TRIM32-ATG7 axis to maintain intracellular homeostasis and to protect cells exposed to pathological conditions from stress-induced tissue damage.
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Estresse Oxidativo , Ubiquitina-Proteína Ligases , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ubiquitinação , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , AutofagiaRESUMO
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by amyloid-ß (Aß) deposition and neurofibrillary tangles. Although the NAD+ -dependent deacetylases SIRT1 and SIRT2 play pivotal roles in age-related diseases, their cooperative effects in AD have not yet been elucidated. Here, we report that the SIRT2:SIRT1 ratio is elevated in the brains of aging mice and in the AD mouse models. In HT22 mouse hippocampal neuronal cells, Aß challenge correlates with decreased SIRT1 expression, while SIRT2 expression is increased. Overexpression of SIRT1 prevents Aß-induced neurotoxicity. We find that SIRT1 impedes SIRT2-mediated APP deacetylation by inhibiting the binding of SIRT2 to APP. Deletion of SIRT1 reduces APP recycling back to the cell surface and promotes APP transiting toward the endosome, thus contributing to the amyloidogenic processing of APP. Our findings define a mechanism for neuroprotection by SIRT1 through suppression of SIRT2 deacetylation, and provide a promising avenue for therapeutic intervention of AD.
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Doença de Alzheimer , Sirtuína 1 , Camundongos , Animais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismo , Acetilação , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismoRESUMO
Sophora moorcroftiana is a leguminous plant endemic to the Qinghai-Tibet Plateau. It has excellent abiotic stress tolerance and is considered an ideal species for local ecological restoration. However, the lack of genetic diversity in the seed traits of S. moorcroftiana hinders its conservation and utilization on the plateau. Therefore, in this study, genotypic variation and phenotypic correlations were estimated for nine seed traits among 15 accessions of S. moorcroftiana over two years, 2014 and 2019, respectively from 15 sample points. All traits evaluated showed significant (P< 0.05) genotypic variation. In 2014, accession mean repeatability was high for seed perimeter, length, width, and thickness, and 100-seed weight. In 2019, mean repeatability for seed perimeter and thickness, and 100-seed weight were high. The estimates of mean repeatability for seed traits across the two years ranged from 0.382 for seed length to 0.781 for seed thickness. Pattern analysis showed that 100-seed weight was significantly positively correlated with traits such as seed perimeter, length, width, and thickness, and identified populations with breeding pool potential. In the biplot, principal components 1 and 2 explained 55.22% and 26.72% of the total variation in seed traits, respectively. These accessions could produce breeding populations for recurrent selection to develop S. moorcroftiana varieties suitable for restoring the fragile ecological environment of the Qinghai-Tibet Plateau.
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AIMS: To understanding the net regional, national, and economic effect of global population ageing on diabetes and its trends during 1990 and 2019 worldwide. METHODS: We employed a decomposition method to estimate the impact of population ageing on diabetes-related disability-adjusted life years (DALYs) and total deaths in 204 countries from 1990 to 2019 at the global, regional, and national level. This method separated the net effect of population ageing from population growth and changes in mortality. RESULTS: Globally, population ageing has become the major contributor to diabetes-related deaths since 2013. The increases in diabetes-related deaths attributed to population ageing exceeding the decreases in mortality change. Population ageing produced an additional 0.42 million diabetes-related deaths and 14.95 million DALYs from 1990 to 2019. At the regional level, population ageing is associated with the increases in diabetes-related deaths in 18 out of 22 regions. The highest increase in diabetes-related deaths attributed to population ageing occurred in men in East Asia (136.31%) and women in Central Latin America (118.58%). The proportion of diabetes-related deaths and DALYs attributable to population ageing showed a bell-shaped relationship with sociodemographic index (SDI) and peaked at high-middle-SDI countries. CONCLUSIONS: The decreases in diabetes-related deaths attributed to mortality change exceeded the increases attributed to population ageing between 1990 and 2019 globally and regionally. The diabetes-related deaths in high-middle-SDI countries were most impacted by population ageing.
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Diabetes Mellitus , Anos de Vida Ajustados por Deficiência , Masculino , Humanos , Feminino , Anos de Vida Ajustados por Qualidade de Vida , Envelhecimento , Fatores de RiscoRESUMO
Background: Chloroplast genomes are usually circular molecules, and most of them are tetrad structures with two inverted repeat (IR) regions, a large single-copy region, and a small single-copy region. IR contraction and expansion are among the genetic diversities during the evolution of plant chloroplast genomes. The only previously released tool for the visualization of junction sites of the regions does not consider the diversity of the starting point of genomes, which leads to incorrect results or even no results for the examination of IR contraction and expansion. Results: In this work, a new tool named CPJSdraw was developed for visualizing the junction sites of chloroplast genomes. CPJSdraw can format the starting point of the irregular linearized genome, correct the junction sites of IR and single-copy regions, display the tetrad structure, visualize the junction sites of any number (≥1) of chloroplast genomes, show the transcription direction of genes adjacent to junction sites, and indicate the IR expansion or contraction of chloroplast genomes. Conclusions: CPJSdraw is a software that is universal and reliable in analysis and visualization of IR expansion or contraction of chloroplast genomes. CPJSdraw has more accurate analysis and more complete functions when compared with previously released tool. CPJSdraw as a perl package and tested data are available at http://dx.doi.org/10.5281/zenodo.7669480 for English users. In addition, an online version with a Chinese interface is available at http://cloud.genepioneer.com:9929/#/tool/alltool/detail/335.
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Genoma de Cloroplastos , Genoma de Cloroplastos/genética , Filogenia , Genoma de Planta/genética , Cloroplastos/genéticaRESUMO
Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression for further interaction with CtIP for DDR, which promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that de-ubiquitination of SAMHD1 by USP7 promotes DDR to overcome oncogenic stress and affect chemotherapy sensitivity.
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Dano ao DNA , Reparo do DNA , Humanos , Peptidase 7 Específica de Ubiquitina/genética , Proteína 1 com Domínio SAM e Domínio HD/genética , UbiquitinaçãoRESUMO
It is emerging that autophagy-related proteins regulate the adaptive response to DNA damage in maintaining genome stability at multiple pathways. Here, we discuss recent insights into how autophagy-related proteins participate in DNA damage repair processes, influence chromosomal instability, and regulate the cell cycle through autophagy-dependent and independent actions. There is increasing awareness of the importance of these pathways mediated by autophagy-related proteins to DNA damage response (DDR), and disturbances in these regulatory connections may be linked to genomic instability participated in various human diseases, such as cancer and aging.
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Reparo do DNA , Instabilidade Genômica , Autofagia/genética , Proteínas Relacionadas à Autofagia , Dano ao DNA/genética , Reparo do DNA/genética , Instabilidade Genômica/genética , HumanosRESUMO
Aging is a primary risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). SIRT2, an NAD+(nicotinamide adenine dinucleotide)-dependent deacetylase, accumulates in the aging brain. Here, we report that, in the amyloid precursor protein (APP)/PS1 transgenic mouse model of AD, genetic deletion of SIRT2 or pharmacological inhibition of SIRT2 ameliorates cognitive impairment. We find that suppression of SIRT2 enhances acetylation of APP, which promotes non-amyloidogenic processing of APP at the cell surface, leading to increased soluble APP-α (sAPPα). We discover that lysines 132 and 134 of the major pathogenic protein ß-amyloid (Aß) precursor are acetylated and that these residues are deacetylated by SIRT2. Strikingly, exogenous expression of wild-type or an acetylation-mimic APP mutant protects cultured primary neurons from Aß42 challenge. Our study identifies SIRT2-mediated deacetylation of APP on K132 and K134 as a regulated post-translational modification (PTM) and suggests inhibition of SIRT2 as a potential therapeutic strategy for AD.
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Doença de Alzheimer , Disfunção Cognitiva , Acetilação , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Presenilina-1/metabolismo , Processamento de Proteína Pós-Traducional , Sirtuína 2/genética , Sirtuína 2/metabolismoRESUMO
Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24-/- mice, a mouse model of progeria. Mechanistically, progerin mislocalizes outside of the nucleus, interacts with the IGF-1R, and down-regulates its expression, leading to inhibited mitochondrial respiration, retarded cell growth, and accelerated cellular senescence. Pharmacological treatment with the PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibitor bpV (HOpic) increases Akt activity and improves multiple abnormalities in Zmpste24-deficient mice. These findings provide previously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS and might be useful for treating LMNA-associated progeroid disorders.
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Reactive oxygen species (ROS) act as a signaling intermediate to promote cellular adaptation to maintain homeostasis by regulating autophagy during pathophysiological stress. However, the mechanism by which ROS promotes autophagy is still largely unknown. Here, we show that the ATM/CHK2/ULK1 axis initiates autophagy to maintain cellular homeostasis by sensing ROS signaling under metabolic stress. We report that ULK1 is a physiological substrate of CHK2, and that the binding of CHK2 to ULK1 depends on the ROS signal and the phosphorylation of threonine 68 of CHK2 under metabolic stress. Further, CHK2 phosphorylates ULK1 on serine 556, and this phosphorylation is dependent on the ATM/CHK2 signaling pathway. CHK2-mediated phosphorylation of ULK1 promotes autophagic flux and inhibits apoptosis induced by metabolic stress. Taken together, these results demonstrate that the ATM/CHK2/ULK1 axis initiates an autophagic adaptive response by sensing ROS, and it protects cells from metabolic stress-induced cellular damage.
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Androgen receptor (AR) signaling drives prostate cancer (PC) progression. Androgen deprivation therapy (ADT) is temporally effective, whereas drug resistance inevitably develops. Abnormal expression of AR/ARV7 (the most common AR splicing variant) is critical for endocrine resistance, while the detailed mechanism is still elusive. In this study, bioinformatics and immunohistochemical analyses demonstrate that RNF8 is high expressed in PC and castration-resistant PC (CRPC) samples and the expression of RNF8 is positively correlated with the Gleason score. The high expression of RNF8 in PCs predicts a poor prognosis. These results provide a potential function of RNF8 in PC progression. Furthermore, the mRNA expression of RNF8 is positively correlated with that of AR in PC. Mechanistically, we find that RNF8 upregulates c-Myc-induced AR transcription via altering histone modifications at the c-Myc binding site within the AR gene. RNF8 also acts as a co-activator of AR, promoting the recruitment of AR/ARV7 to the KLK3 (PSA) promoter, where RNF8 modulates histone modifications. These functions of RNF8 are dependent on its E3 ligase activity. RNF8 knockdown further reduces AR transactivation and PSA expression in CRPC cells with enzalutamide treatment. RNF8 depletion restrains cell proliferation and alleviates enzalutamide resistance in CRPC cells. Our findings indicate that RNF8 may be a potential therapeutic target for endocrine resistance in PC.
Assuntos
Proteínas de Ligação a DNA , Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Ubiquitina-Proteína Ligases , Antagonistas de Androgênios/uso terapêutico , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Humanos , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Regulação para CimaRESUMO
The lamellar body (LB), a concentric structure loaded with surfactant proteins and phospholipids, is an organelle specific to type 2 alveolar epithelial cells (AT2). However, the origin of LBs has not been fully elucidated. We have previously reported that autophagy regulates Weibel-Palade bodies (WPBs) formation, and here we demonstrated that autophagy is involved in LB maturation, another lysosome-related organelle. We found that during development, LBs were transformed from autophagic vacuoles containing cytoplasmic contents such as glycogen. Fusion between LBs and autophagosomes was observed in wild-type neonate mice. Moreover, the markers of autophagic activity, microtubule-associated protein 1 light chain 3B (LC3B), largely co-localized on the limiting membrane of the LB. Both autophagy-related gene 7 (Atg7) global knockout and conditional Atg7 knockdown in AT2 cells in mice led to defects in LB maturation and surfactant protein B production. Additionally, changes in autophagic activity altered LB formation and surfactant protein B production. Taken together, these results suggest that autophagy plays a critical role in the regulation of LB formation during development and the maintenance of LB homeostasis during adulthood.
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Células Epiteliais Alveolares , Surfactantes Pulmonares , Animais , Autofagia/genética , Corpos Lamelares , Lisossomos/metabolismo , Camundongos , Surfactantes Pulmonares/metabolismo , Tensoativos/metabolismoRESUMO
In multiple types of cancer, decreased tumour cell apoptosis during chemotherapy is indicative of decreased chemosensitivity. Forkhead box K2 (FOXK2), which is essential for cell fate, regulates cancer cell apoptosis through several post-translational modifications. However, FOXK2 acetylation has not been extensively studied. Here, we evaluated the effects of sirtiun 1 (SIRT1) on FOXK2 deacetylation. Our findings demonstrated that SIRT1 inhibition increased FOXK2-induced chemosensitivity to cisplatin and that K223 in FOXK2 was acetylated. Furthermore, FOXK2 K223 deacetylation reduced chemosensitivity to cisplatin in vitro and in vivo. Mechanistically, FOXK2 was acetylated by the acetyltransferase cAMP response element binding protein and deacetylated by SIRT1. Furthermore, cisplatin attenuated the interaction between FOXK2 and SIRT1. Cisplatin or SIRT1 inhibition enhanced FOXK2 acetylation, thereby reducing the nuclear distribution of FOXK2. Additionally, FOXK2 K223 acetylation significantly affected the expression of cell cycle-related and apoptosis-related genes in cisplatin-stimulated cancer cells, and FOXK2 K223 hyperacetylation promoted mitotic catastrophe, which enhanced chemosensitivity to cisplatin. Overall, our results provided insights into the mechanisms of SIRT1-mediated FOXK2 deacetylation, which was involved in chemosensitivity to cisplatin.