CDK1 and CCNA2 play important roles in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a malignant tumor that occurs in oral cavity and is dominated by squamous cells. The relationship between CDK1, CCNA2, and OSCC is still unclear. The OSCC datasets GSE74530 and GSE85195 configuration files were downloaded from the Gene Expression Omnibus (GEO) database and were derived from platforms GPL570 and GPL6480. Differentially expressed genes (DEGs) were screened. The weighted gene co-expression network analysis, functional enrichment analysis, gene set enrichment analysis, construction and analysis of protein-protein interaction (PPI) network, Comparative Toxicogenomics Database analysis were performed. Gene expression heatmap was drawn. TargetScan was used to screen miRNAs that regulate central DEGs. A total of 1756 DEGs were identified. According to Gene Ontology (GO) analysis, they were predominantly enriched in processes related to organic acid catabolic metabolism, centromeric, and chromosomal region condensation, and oxidoreductase activity. In Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the DEGs were mainly concentrated in metabolic pathways, P53 signaling pathway, and PPAR signaling pathway. Weighted gene co-expression network analysis was performed with a soft-thresholding power set at 9, leading to the identification of 6 core genes (BUB1B, CCNB1, KIF20A, CCNA2, CDCA8, CDK1). The gene expression heatmap revealed that core genes (CDK1, CCNA2) were highly expressed in OSCC samples. Comparative Toxicogenomics Database analysis demonstrated associations between the 6 genes (BUB1B, CCNB1, KIF20A, CCNA2, CDCA8, CDK1) and oral tumors, precancerous lesions, inflammation, immune system disorders, and tongue tumors. The associated miRNAs for CDK1 gene were hsa-miR-203a-3p.2, while for CCNA2 gene, they were hsa-miR-6766-3p, hsa-miR-4782-3p, and hsa-miR-219a-5p. CDK1 and CCNA2 are highly expressed in OSCC. The higher the expression of CDK1 and CCNA2, the worse the prognosis.

Long Non-Coding RNA-Cardiac-Inducing RNA 6 Mediates Repair of Infarcted Hearts by Inducing Mesenchymal Stem Cell Differentiation into Cardiogenic Cells through Cyclin-Dependent Kinase 1.

This study aims to investigate the induction effect of LncRNA-CIR6 on MSC differentiation into cardiogenic cells in vitro and in vivo. In addition to pretreatment with Ro-3306 (a CDK1 inhibitor), LncRNA-CIR6 was transfected into BMSCs and hUCMSCs using jetPRIME. LncRNA-CIR6 was further transfected into the hearts of C57BL/6 mice via 100 µL of AAV9-cTnT-LncRNA-CIR6-ZsGreen intravenous injection. After three weeks of transfection followed by AMI surgery, hUCMSCs (5 × 105/100 µL) were injected intravenously one week later. Cardiac function was evaluated using VEVO 2100 and electric mapping nine days after cell injection. Immunofluorescence, Evans blue-TTC, Masson staining, FACS, and Western blotting were employed to determine relevant indicators. LncRNA-CIR6 induced a significant percentage of differentiation in BMSCs (83.00 ± 0.58)% and hUCMSCs (95.43 ± 2.13)% into cardiogenic cells, as determined by the expression of cTnT using immunofluorescence and FACS. High cTNT expression was observed in MSCs after transfection with LncRNA-CIR6 by Western blotting. Compared with the MI group, cardiac contraction and conduction function in MI hearts treated with LncRNA-CIR6 or combined with MSCs injection groups were significantly increased, and the areas of MI and fibrosis were significantly lower. The transcriptional expression region of LncRNA-CIR6 was on Chr17 from 80209290 to 80209536. The functional region of LncRNA-CIR6 was located at nucleotides 0-50/190-255 in the sequence. CDK1, a protein found to be related to the proliferation and differentiation of cardiomyocytes, was located in the functional region of the LncRNA-CIR6 secondary structure (from 0 to 17). Ro-3306 impeded the differentiation of MSCs into cardiogenic cells, while MSCs transfected with LncRNA-CIR6 showed a high expression of CDK1. LncRNA-CIR6 mediates the repair of infarcted hearts by inducing MSC differentiation into cardiogenic cells through CDK1.

Lethal Giant Disc is a target of Cdk1 and regulates ESCRT-III localization during germline stem cell abscission.

Abscission is the final step of cytokinesis that allows the physical separation of sister cells through the scission of the cellular membrane. This deformation is driven by ESCRT-III proteins, which can bind membranes and form dynamic helices. A crucial step in abscission is the recruitment of ESCRT-III proteins at the right time and place. Alix is one of the best characterized proteins that recruits ESCRT-III proteins from yeast to mammals. However, recent studies in vivo have revealed that pathways acting independently or redundantly with Alix are also required at abscission sites in different cellular contexts. Here, we show that Lgd acts redundantly with Alix to properly localize ESCRT-III to the abscission site in germline stem cells (GSCs) during Drosophila oogenesis. We further demonstrate that Lgd is phosphorylated at multiple sites by the CycB/Cdk1 kinase. We found that these phosphorylation events potentiate the activity of Shrub, a Drosophila ESCRT-III, during abscission of GSCs. Our study reveals that redundancy between Lgd and Alix, and coordination with the cell cycle kinase Cdk1, confers robust and timely abscission of Drosophila germline stem cells.

Deciphering congenital heart defects, facial dysmorphism and intellectual developmental disorder (CHDFIDD) associated with constitutional CDK13 pathogenic variants - case report and literature review.

There are 21 human cyclin-dependent kinases which are involved in regulation of the cell cycle, transcription, RNA splicing, apoptosis and neurogenesis. Five of them: CDK4, CDK5, CDK6, CDK10 and CDK13 are associated with human phenotypes. To date, only 62 patients have been presented with mutated CDK13 gene. Those patients had developmental delay, dysmorphic facial features, feeding difficulties, different structural heart and brain defects. 36 of them had missense mutation affecting the protein kinase domain of CDK13. Our patient is the first person reported so far with a frameshift mutation which introduce premature stop codon in the first exon of the CDK13 gene. She has symptoms characteristic for congenital heart defects, facial dysmorphism and intellectual developmental disorder (CHDFIDD).

Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC-MS/MS cancer cell entrapment assays.

Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient-related factors while others are inclined to attribute this as a DAA side-effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell-cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in-house developed and validated LC-MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti-proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti-proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.

Recombinant cyclin B-Cdk1-Suc1 capable of multi-site mitotic phosphorylation in vitro.

Cyclin-dependent kinase 1 (Cdk1) complexed with cyclin B phosphorylates multiple sites on hundreds of proteins during mitosis. However, it is not fully understood how multi-site mitotic phosphorylation by cyclin B-Cdk1 controls the structures and functions of individual substrates. Here we develop an easy-to-use protocol to express recombinant vertebrate cyclin B and Cdk1 in insect cells from a single baculovirus vector and to purify their complexes with excellent homogeneity. A series of in-vitro assays demonstrate that the recombinant cyclin B-Cdk1 can efficiently and specifically phosphorylate the SP and TP motifs in substrates. The addition of Suc1 (a Cks1 homolog in fission yeast) accelerates multi-site phosphorylation of an artificial substrate containing TP motifs. Importantly, we show that mitosis-specific multi-subunit and multi-site phosphorylation of the condensin I complex can be recapitulated in vitro using recombinant cyclin B-Cdk1-Suc1. The materials and protocols described here will pave the way for dissecting the biochemical basis of critical mitotic processes that accompany Cdk1-mediated large-scale phosphorylation.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation.

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

OTUD4 promotes the progression of glioblastoma by deubiquitinating CDK1 and activating MAPK signaling pathway.

Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global burden of GBM is increasing notably due to limited treatment options, drug delivery problems, and the lack of characteristic molecular targets. OTU deubiquitinase 4 (OTUD4) is a potential predictive factor for several cancers such as breast cancer, liver cancer, and lung cancer. However, its function in GBM remains unknown. In this study, we found that high expression of OTUD4 is positively associated with poor prognosis in GBM patients. Moreover, we provided in vitro and in vivo evidence that OTUD4 promotes the proliferation and invasion of GBM cells. Mechanism studies showed that, on the one hand, OTUD4 directly interacts with cyclin-dependent kinase 1 (CDK1) and stabilizes CDK1 by removing its K11, K29, and K33-linked polyubiquitination. On the other hand, OTUD4 binds to fibroblast growth factor receptor 1 (FGFR1) and reduces FGFR1's K6 and K27-linked polyubiquitination, thereby indirectly stabilizing CDK1, ultimately influencing the activation of the downstream MAPK signaling pathway. Collectively, our results revealed that OTUD4 promotes GBM progression via OTUD4-CDK1-MAPK axis, and may be a prospective therapeutic target for GBM treatment.

Increases in cyclin A/Cdk activity and in PP2A-B55 inhibition by FAM122A are key mitosis-inducing events.

Entry into mitosis has been classically attributed to the activation of a cyclin B/Cdk1 amplification loop via a partial pool of this kinase becoming active at the end of G2 phase. However, how this initial pool is activated is still unknown. Here we discovered a new role of the recently identified PP2A-B55 inhibitor FAM122A in triggering mitotic entry. Accordingly, depletion of the orthologue of FAM122A in C. elegans prevents entry into mitosis in germline stem cells. Moreover, data from Xenopus egg extracts strongly suggest that FAM122A-dependent inhibition of PP2A-B55 could be the initial event promoting mitotic entry. Inhibition of this phosphatase allows subsequent phosphorylation of early mitotic substrates by cyclin A/Cdk, resulting in full cyclin B/Cdk1 and Greatwall (Gwl) kinase activation. Subsequent to Greatwall activation, Arpp19/ENSA become phosphorylated and now compete with FAM122A, promoting its dissociation from PP2A-B55 and taking over its phosphatase inhibition role until the end of mitosis.

Myt1 kinase inhibitors - Insight into structural features, offering potential frameworks.

The cell cycle includes two checkpoint arrests allowing to repair of damaged DNA. Many cancer cell lines exhibit weak G1 checkpoint mechanisms relying significantly more on the G2 checkpoint than do healthy cells. Inhibition of Myt1 kinase (PKMYT1), a forgotten member of the Wee family, cyclin-dependent kinase 1 (Cdk1) inhibitory kinase, target for G2 checkpoint abrogation, whose inhibition forces cells into premature unchecked mitosis resulting in cell death, is a promising concept for anticancer therapy. There are not many inhibitors of this emerging, potentially clinically important kinase. Herein, the valuable insight into structural features and binding mechanisms of diaminopyrimidines, aminoquinolines, quinazolines, pyrido[2,3-d]pyrimidines, pyrazolo[3,4-d]pyrimidines, and pyrrolo[2,3-b]quinoxalines, as well as finally made a general scheme of fragmented structures of Myt1 inhibitors with the enzyme, offer potential frameworks useful for future directions, for further chemical optimizations, in the discovery and the design of novel effective structures, potential therapeutics.

Curcumin targets miR-134-5p to suppress the progression of colorectal cancer through regulating the CDCA3/CDK1 pathway.

It has been reported the anti-tumor action of curcumin on colorectal cancer. In this study, we aimed to explore the potential mechanisms underlying curcumin in the development of colorectal cancer. CCK-8, EdU, flow cytometry, and transwell invasion assays were conducted to investigate the function role of curcumin in cell proliferation, apoptosis, and invasion. The level of miR-134-5p and CDCA3 was determined using RT-qPCR analysis. Western blot was applied for detecting the levels of c-myc, MMP9, CDCA3, and CDK1. Dual-luciferase reporter assay was used to evaluate the relationship between miR-134-5p and CDCA3, and IP assay was performed to examine the interaction between CDCA3 and CDK1. Additionally, SW620 cells were injected into the mice to form the xenograft tumor model. Curcumin treatment repressed cell growth and invasion, and induced cell apoptosis in HCT-116 and SW620 cells. Curcumin elevated miR-134-5p expression and restrained CDCA3 expression in HCT-116 and SW620 cells. MiR-134-5p inhibitor or CDCA3 overexpression could restore the effects of curcumin on cell growth, apoptosis, and invasion in HCT-116 and SW620 cells. MiR-134-5p targeted CDCA3, and CDCA3 could rescue the repressive effects of miR-134-5p on the progression of colorectal cancer. Moreover, CDCA3 interacted with CDK1, and CDK1 overexpression blocked the suppressive effects of CDCA3 downregulation on the development of colorectal cancer. In addition, curcumin treatment repressed tumor growth in colorectal cancer via increasing miR-134-5p and downregulating CDCA3 and CDK1 expression in vivo. Our findings provided the evidence that curcumin upregulated miR-134-5p to inhibit the progression of colorectal cancer by regulating CDCA3/CDK1 pathway.

Computational molecular perspectives on novel carbazole derivative as an anti-cancer molecule against CDK1 of breast and colorectal cancers via gene expression studies, novel two-way docking strategies, molecular mechanics and dynamics.

With increase in cancer incidences, alternative strategies for disease management are of utmost importance. Carbazole, is a compound that is being studied extensively as an anti-cancer compound. In this work, we aimed to investigate a carbazole derivative against specific cancer types such as breast and colorectal, based on the off-target analyses of carbazole derivative. The present work shortlisted 6 proteins that have an association in both cancer types, and then employed two different molecular docking strategies to examine the binding stability of carbazole derivative: a blind-docking state, where the pockets were undefined and mutation-docking state, where possible mutations were induced within the proteins. The results showed that CDK1 bound best in both states to carbazole derivative, and performed better than an array of positive controls. Molecular dynamic simulations at 100 ns further proved its stability, with carbazole derivative-CDK1-blind and mutated complex having RMSD values between 3.2 and 3.6 Å, and 2.8-3.2 Šrespectively. Molecular-mechanics generalized born and surface area solvation disclosed free energy of binding for the complexes as -28.79 ± 3.97 kcal/mol and -31.86 ± 5.09 kcal/mol respectively, with carbazole derivative bound stably within the binding pocket at every 10 ns of the 100 ns trajectory. Radial distribution functions showed that the bell curve was well within 6 Å, thus showing that carbazole derivative and its atoms do not deviate away from the pocket, suggesting its ability to be used as a good anti-cancer compound against breast and colorectal.

Leukocyte-poor platelet-rich plasma and leukocyte-rich platelet-rich plasma promote myoblast proliferation through the upregulation of cyclin A, cdk1, and cdk2.

Muscle injuries are common among athletes and often treated with platelet-rich plasma (PRP). However, whether the leukocyte concentration affects the efficacy of PRP in treating muscle injuries remains unclear. This study investigated the effects of leukocyte-poor platelet-rich plasma (LP-PRP) and leukocyte-rich platelet-rich plasma (LR-PRP) on myoblast proliferation and the molecular mechanisms underlying these effects. Myoblasts were treated with 0.5% LP-PRP, 0.5% LR-PRP, 1% LP-PRP, or 1% LR-PRP for 24 h. The gene expression of the LP-PRP- and LR-PRP-treated myoblasts was determined using RNA sequencing analysis. Cell proliferation was evaluated using an bromodeoxyuridine (BrdU) assay, and cell cycle progression was assessed through flow cytometry. The expression of cyclin A, cyclin-dependent kinase 1 (cdk1), and cdk2 was examined using Western blotting. The expression of myoblast determination protein 1 (MyoD1) was examined through Western blotting and immunofluorescence staining. The LP-PRP and LR-PRP both promoted the proliferation of myoblasts and increased differential gene expression of myoblasts. Moreover, the LP-PRP and LR-PRP substantially upregulated the expression of cyclin A, cdk1, and cdk2. MyoD1 expression was induced in the LP-PRP and LR-PRP-treated myoblasts. Our results corroborate the finding that LP-PRP and LR-PRP have similar positive effects on myoblast proliferation and MyoD1 expression.

Targeting Cyclin-Dependent Kinase 1 Induces Apoptosis and Cell Cycle Arrest of Activated Hepatic Stellate Cells.

Liver fibrosis is the integral process of chronic liver diseases caused by multiple etiologies and characterized by excessive deposition of extracellular matrix (ECM). During liver fibrosis, hepatic stellate cells (HSCs) transform into a highly proliferative, activated state, producing various cytokines, chemokines, and ECM. However, the precise mechanisms that license HSCs into the highly proliferative state remain unclear. Cyclin-dependent kinase 1 (CDK1) is a requisite event for the transition of the G1/S and G2/M phases in eukaryotic cells. In this study, it is demonstrated that CDK1 and its activating partners, Cyclin A2 and Cyclin B1, are upregulated in both liver fibrosis/cirrhosis patient specimens and the murine hepatic fibrosis models, especially in activated HSCs. In vitro, CDK1 is upregulated in spontaneously activated HSCs, and inhibiting CDK1 with specific small-molecule inhibitors (CGP74514A, RO-3306, or Purvalanol A) orshort hairpin RNAs (shRNAs) resulted in HSC apoptosis and cell cycle arrest by regulating Survivin expression. Above all, it is illustrated that increased CDK1 expression licenses the HSCs into a highly proliferative state and can serve as a potential therapeutic target in liver fibrosis.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

Identification of CDK1, PBK, and CHEK1 as an Oncogenic Signature in Glioblastoma: A Bioinformatics Approach to Repurpose Dapagliflozin as a Therapeutic Agent.

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells' presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle's main regulatory proteins. Herein, we identified and validated the biomarker and predictive properties of a chemoradio-resistant oncogenic signature in GBM comprising CDK1, PBK, and CHEK1 through our comprehensive in silico analysis. We found that CDK1/PBK/CHEK1 overexpression drives the cell cycle, subsequently promoting GBM tumor progression. In addition, our Kaplan-Meier survival estimates validated the poor patient survival associated with an overexpression of these genes in GBM. We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib.

PARP Inhibitor Sensitizes BRCA-mutant Pancreatic Cancer to Oxaliplatin by Suppressing the CDK1/BRCA1 Axis.

BACKGROUND/AIM: Currently, olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has been approved as maintenance therapy for patients with germline BRCA mutations and metastatic pancreatic cancer. However, platinum-based chemotherapy, which induces synthetic lethality with PARP inhibitor treatment, is still controversial. Hence, we aimed to examine a platinum-based drug in combination with a PARP inhibitor and generate data regarding the use of a PARP inhibitor in the overall treatment of pancreatic cancer. MATERIALS AND METHODS: Using the Capan-1 cell line (BRCA2-mutant pancreatic cancer cell line), we evaluated the combinatorial effects of olaparib, a PARP inhibitor, and oxaliplatin by cell viability, combination index, western blotting, immunocytochemistry, flow cytometry, apoptosis assays and in vivo experiments. RESULTS: Capan-1 cells showed high sensitivity to olaparib due to the alteration in PARP activity, which led to cell death through the accumulation of oxaliplatin-induced DNA damage. Beyond DNA damage, oxaliplatin also suppressed the CDK1/BRCA1 signaling axis, which induced defects in homologous recombination repair. Additionally, inhibition of CDK1, a biomarker for oxaliplatin efficacy, induced cell death regardless of the BRCA mutation profile. CONCLUSION: Oxaliplatin may be used in combination with olaparib in PDAC patients with DNA damage repair mutations. Our findings highlight CDK1 as a potential therapeutic target for pancreatic cancer.

CDK1-SRC Interaction-Dependent Transcriptional Activation of HSP90AB1 Promotes Antitumor Immunity in Hepatocellular Carcinoma.

This study aimed to analyze multiomics data and construct a regulatory network involving kinases, transcription factors, and immune genes in hepatocellular carcinoma (HCC) prognosis. The researchers used transcriptomic, proteomic, and clinical data from TCGA and GEO databases to identify immune genes associated with HCC. Statistical analysis, meta-analysis, and protein-protein interaction analyses were performed to identify key immune genes and their relationships. In vitro and in vivo experiments validated the CDK1-SRC-HSP90AB1 network's effects on HCC progression and antitumor immunity. A prognostic risk model was developed using clinicopathological features and immune infiltration. The immune genes LPA, BIRC5, HSP90AB1, ROBO1, and CCL20 were identified as the key prognostic factors. The CDK1-SRC-HSP90AB1 network promoted HCC cell proliferation and migration, with HSP90AB1 being transcriptionally activated by the CDK1-SRC interaction. Manipulating SRC or HSP90AB1 reversed the effects of CDK1 and SRC on HCC. The CDK1-SRC-HSP90AB1 network also influenced HCC tumor formation and antitumor immunity. Overall, this study highlights the importance of the CDK1-SRC-HSP90AB1 network as a crucial immune-regulatory network in the HCC prognosis.

The Cyclin-dependent kinase 1: more than a cell cycle regulator.

The Cyclin-dependent kinase 1, as a serine/threonine protein kinase, is more than a cell cycle regulator as it was originally identified. During the last decade, it has been shown to carry out versatile functions during the last decade. From cell cycle control to gene expression regulation and apoptosis, CDK1 is intimately involved in many cellular events that are vital for cell survival. Here, we provide a comprehensive catalogue of the CDK1 upstream regulators and substrates, describing how this kinase is implicated in the control of key 'cell cycle-unrelated' biological processes. Finally, we describe how deregulation of CDK1 expression and activation has been closely associated with cancer progression and drug resistance.

CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.