KIF22 promotes multiple myeloma progression by regulating the CDC25C/CDK1/cyclinB1 pathway.

PURPOSE: Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal proliferation of malignant plasma B cells in bone marrow, and its pathogenesis remains unknown. The aim of this study was to determine the role of kinesin family member 22 (KIF22) in MM and elucidate its molecular mechanism. METHODS: The expression of KIF22 was detected in MM patients based upon the public datasets and clinical samples. Then, in vitro assays were performed to investigate the biological function of KIF22 in MM cell lines, and subcutaneous xenograft models in nude mice were conducted in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay were used to determine the mechanism of KIF22-mediated regulation. RESULTS: The results demonstrated that the expression of KIF22 in MM patients was associated with several clinical features, including gender (P = 0.016), LDH (P < 0.001), ß2-MG (P = 0.003), percentage of tumor cells (BM) (P = 0.002) and poor prognosis (P < 0.0001). Furthermore, changing the expression of KIF22 mainly influenced the cell proliferation in vitro and tumor growth in vivo, and caused G2/M phase cell cycle dysfunction. Mechanically, KIF22 directly transcriptionally regulated cell division cycle 25C (CDC25C) by binding its promoter and indirectly influenced CDC25C expression by regulating the ERK pathway. KIF22 also regulated CDC25C/CDK1/cyclinB1 pathway. CONCLUSION: KIF22 could promote cell proliferation and cell cycle progression by transcriptionally regulating CDC25C and its downstream CDC25C/CDK1/cyclinB1 pathway to facilitate MM progression, which might be a potential therapeutic target in MM.

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.

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.

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.

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.

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.

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.

Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis.

BACKGROUND: Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with the initiation and progression of Triple-negative breast cancer (TNBC). The publicly available TCGA database of breast cancer data was used to analyze the OTUD deubiquitinating family members that were correlated with survival of breast cancer and ovarian tumor domain-containing 2 (OTUD-2), or YOD1 was identified. The aim of present study was to assess YOD1 expression and function in human TNBC and then explored the underlying molecular events. METHODS: We detected the expression of YOD1 in 32 TNBC and 44 NTNBC samples by qRT-PCR, Western blot and immunohistochemistry. Manipulation of YOD1 expression was assessed in vitro and in vivo for TNBC cell proliferation, migration, invasion, cell-cycle and drug resistance, using colony formation assay, transwell assay, CCK8 assay, TUNEL assay, flow cytometric analysis and xenograft tumor assay. Next, proteomic analysis, Western blot, proximity ligation assay, Immunoprecipitation, and Immunofluorescence were conducted to assess downstream targets. RESULTS: It was found that YOD1 was significantly upregulated in TNBC tissues compared with non-triple-negative breast cancer (NTNBC), which was positively correlated with poor survival in TNBC patients. Knockdown of YOD1 effectively inhibited TNBC cell migration, proliferation, cell cycle and resistance to cisplatin and paclitaxel. Mechanistically, YOD1 promoted TNBC progression in a manner dependent on its catalytic activity through binding with CDK1, leading to de-polyubiquitylation of CDK1 and upregulation of CDK1 expression. In addition, YOD1 overexpression was found to be correlated with CDK1 overexpression in human TNBC specimens. Finally, in vivo study demonstrated that YOD1 knockdown or YOD1 inhibitor could inhibit CDK1 expression and suppress the growth and metastasis of TNBC tumors. CONCLUSION: Our study highlights that YOD1 functions as an oncogene in TNBC via binding to CDK1 and mediated its stability and oncogenic activity. Interfering with YOD1 expression or YOD1 inhibitor could suppress TNBC cells in vitro and in vivo, suggesting that YOD1 may prove to be a promising therapeutic target for TNBC.

The super-enhancer-driven lncRNA LINC00880 acts as a scaffold between CDK1 and PRDX1 to sustain the malignance of lung adenocarcinoma.

Super-enhancers (SEs) are regulatory element clusters related to cell identity and disease. While the studies illustrating the function of SE-associated long noncoding RNAs (lncRNAs) in lung adenocarcinoma (LUAD) remains few. In our research, a SE-driven lncRNA, LINC00880, was identified, which showed higher expression in LUAD compared to normal tissues and indicated worse outcomes in stage I LUADs. We found that the transcription factor (TF) FOXP3 could simultaneously occupy the promoter and SE regions of LINC00880 to promote its transcription. The oncogenic function of LINC00880 was validated both in vitro and in vivo. Mechanically, LINC00880 binds to the protein CDK1 to increase its kinase activity, which rely on the phosphorylation state of pT161 in CDK1. LINC00880 also promotes the interaction between CDK1 and PRDX1. Moreover, LINC00880 interacts with PRDX1, which indicates that LINC00880 acts as a protein scaffold between CDK1 and PRDX1 to form a ternary complex, thereby resulting in the activation of PI3K/AKT to promote malignancy. Our results reveal that the SE-associated lncRNA LINC00880 regulates the CDK1/PRDX1 axis to sustain the malignancy of LUAD, providing a novel therapeutic target.

Smoothened mediates medaka spermatogonia proliferation via Gli1-Rgcc-Cdk1 axis†.

The proliferation of spermatogonia directly affects spermatogenesis and male fertility, but its underlying molecular mechanisms are poorly understood. In this study, Smoothened (Smo), the central transducer of Hedgehog signaling pathway, was characterized in medaka (Oryzias latipes), and its role and underlying mechanisms in the proliferation of spermatogonia were investigated. Smo was highly expressed in spermatogonia. In ex vivo testicular organ culture and a spermatogonial cell line (SG3) derived from medaka mature testis, Smo activation promoted spermatogonia proliferation, while its inhibition induced apoptosis. The expression of glioma-associated oncogene homolog 1 (gli1) and regulator of cell cycle (rgcc) was significantly upregulated in SG3 after Smo activation. Furthermore, Gli1 transcriptionally upregulated the expression of rgcc, and Rgcc overexpression rescued cell apoptosis caused by Smo or Gli1 inhibition. Co-immunoprecipitation assay indicated that Rgcc could interact with cyclin-dependent kinase 1 (Cdk1) to regulate the cell cycle of spermatogonia. Collectively, our study firstly reveals that Smo mediates the proliferation of spermatogonia through Gli1-Rgcc-Cdk1 axis. In addition, Smo and Gli1 are necessary of the survival of spermatogonia. This study deepens our understanding of spermatogonia proliferation and survival at the molecular level, and provides insights into male fertility control and reproductive disease treatment.

Rucaparib inhibits lung adenocarcinoma cell proliferation and migration via the SHCBP1/CDK1 pathway.

Src homolog and collagen homolog binding protein 1 (SHCBP1) binds to the SH2 domain of SHC-transforming protein 1 (SHC1) and is involved in midbody organization and cytokinesis completion. SHCBP1 has been reported to be a cancer driver gene, promoting cancer progression. However, the functional role and underlying mechanism of SHCBP1 in regulating lung adenocarcinoma (LUAD) cell proliferation and migration are incompletely understood. Here, we discovered that SHCBP1 is overexpressed in LUAD tissues and is associated with a poor prognosis. SHCBP1 knockdown inhibited LUAD cell proliferation and migration by arresting the cell cycle and preventing epithelial-mesenchymal transition (EMT) via decreasing cyclin-dependent kinase 1 (CDK1) expression. Mechanistically, CDK1 overexpression reversed SHCBP1 knockdown-induced inhibition of proliferation and migration, confirming CDK1 as a key downstream target of SHCBP1. In addition, we proposed that rucaparib may be a small-molecule inhibitor of SHCBP1 and validated both in vitro and in vivo that rucaparib inhibits cell proliferation and migration via suppression of the SHCBP1/CDK1 pathway in LUAD. Our study elucidates a newly identified role of SHCBP1 in promoting cell proliferation and migration in LUAD, and suggests rucaparib as a potential inhibitor for LUAD treatment.

Mitotic defects lead to unreduced sperm formation in cdk1-/- mutants.

Unreduced gametes, that are important for species evolution and agricultural development, are generally believed to be formed by meiotic defects. However, we found that male diploid loach (Misgurnus anguillicaudatus) could produce not only haploid sperms, but also unreduced sperms, after cyclin-dependent kinase 1 gene (cdk1, one of the most important kinases in regulating cell mitosis) deletion. Observations on synaptonemal complexes of spermatocyte in prophase of meiosis and spermatogonia suggested that the number of chromosomes in some spermatogonia of cdk1-/- loach doubled, leading to unreduced diploid sperm production. Then, transcriptome analysis revealed aberrant expressions of some cell cycle-related genes (such as ppp1c and gadd45) in spermatogonia of cdk1-/- loach relative to wild-type loach. An in vitro and in vivo experiment further validated that Cdk1 deletion in diploid loach resulted in mitotic defects, leading to unreduced diploid sperm formation. In addition, we found that cdk1-/- zebrafish could also produce unreduced diploid sperms. This study provides important information on revealing the molecular mechanisms behind unreduced gamete formation through mitotic defects, and lays the foundation for a novel strategy for fish polyploidy creation by using cdk1 mutants to produce unreduced sperms, which can then be used to obtain polyploidy, proposed to benefit aquaculture.

Mitotic CDK1 and 4E-BP1 I: Loss of 4E-BP1 serine 82 phosphorylation promotes proliferative polycystic disease and lymphoma in aged or sublethally irradiated mice.

4E-BP1 is a tumor suppressor regulating cap-dependent translation that is in turn controlled by mechanistic target of rapamycin (mTOR) or cyclin-dependent kinase 1 (CDK1) phosphorylation. 4E-BP1 serine 82 (S82) is phosphorylated by CDK1, but not mTOR, and the consequences of this mitosis-specific phosphorylation are unknown. Knock-in mice were generated with a single 4E-BP1 S82 alanine (S82A) substitution leaving other phosphorylation sites intact. S82A mice were fertile and exhibited no gross developmental or behavioral abnormalities, but the homozygotes developed diffuse and severe polycystic liver and kidney disease with aging, and lymphoid malignancies after irradiation. Sublethal irradiation caused immature T-cell lymphoma only in S82A mice while S82A homozygous mice have normal T-cell hematopoiesis before irradiation. Whole genome sequencing identified PTEN mutations in S82A lymphoma and impaired PTEN expression was verified in S82A lymphomas derived cell lines. Our study suggests that the absence of 4E-BP1S82 phosphorylation, a subtle change in 4E-BP1 phosphorylation, might predispose to polycystic proliferative disease and lymphoma under certain stressful circumstances, such as aging and irradiation.

AR-A014418 regulates intronic polyadenylation and transcription of PD-L1 through inhibiting CDK12 and CDK13 in tumor cells.

BACKGROUND: Immune checkpoint molecules, especially programmed death 1 (PD-1) and its ligand, programmed death ligand 1 (PD-L1), protect tumor cells from T cell-mediated killing. Immune checkpoint inhibitors, designed to restore the antitumor immunosurveillance, have exhibited significant clinical benefits for patients with certain cancer types. Nevertheless, the relatively low response rate and acquisition of resistance greatly limit their clinical applications. A deeper understanding of the regulatory mechanisms of PD-L1 protein expression and activity will help to develop more effective therapeutic strategies. METHODS: The effects of AR-A014418 and THZ531 on PD-L1 expression were detected by western blot, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and flow cytometry. In vitro kinase assays with recombinant proteins were performed to confirm that AR-A014418 functioned as a CDK12 and CDK13 dual inhibitor. The roles of CDK12 and CDK13 in intronic polyadenylation (IPA) and transcription of PD-L1 were determined via RNA interference or protein overexpression. T-cell cytotoxicity assays were used to validate the activation of antitumor immunity by AR-A014418 and THZ531. RESULTS: AR-A014418 inhibits CDK12 to enhance the IPA, and inhibits CDK13 to repress the transcription of PD-L1. IPA generates a secreted PD-L1 isoform (PD-L1-v4). The extent of IPA was not enough to reduce full-length PD-L1 expression obviously. Only the superposition of enhancing IPA and repressing transcription (dual inhibition of CDK12 and CDK13) dramatically suppresses full-length PD-L1 induction by interferon-γ. AR-A014418 and THZ531 could potentiate T-cell cytotoxicity against tumor cells. CONCLUSIONS: Our work identifies a new regulatory pathway for PD-L1 expression and discovers CDK12 and CDK13 as promising drug targets for immune modulation and combined therapeutic strategies.

SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis.

The development of androgen receptor signaling inhibitor (ARSI) drug resistance in prostate cancer (PC) remains therapeutically challenging. Our group has described the role of sex determining region Y-box 2 (SOX2) overexpression in ARSI-resistant PC. Continuing this work, we report that NR3C1, the gene encoding glucocorticoid receptor (GR), is a novel SOX2 target in PC, positively regulating its expression. Similar to ARSI treatment, SOX2-positive PC cells are insensitive to GR signaling inhibition using a GR modulating therapy. To understand SOX2-mediated nuclear hormone receptor signaling inhibitor (NHRSI) insensitivity, we performed RNA-seq in SOX2-positive and -negative PC cells following NHRSI treatment. RNA-seq prioritized differentially regulated genes mediating the cell cycle, including G2 checkpoint WEE1 Kinase (WEE1) and cyclin-dependent kinase 1 (CDK1). Additionally, WEE1 and CDK1 were differentially expressed in PC patient tumors dichotomized by high vs low SOX2 gene expression. Importantly, pharmacological targeting of WEE1 (WEE1i) in combination with an ARSI or GR modulator re-sensitizes SOX2-positive PC cells to nuclear hormone receptor signaling inhibition in vitro, and WEE1i combined with ARSI significantly slowed tumor growth in vivo. Collectively, our data suggest SOX2 predicts NHRSI resistance, and simultaneously indicates the addition of WEE1i to improve therapeutic efficacy of NHRSIs in SOX2-positive PC.

Cuproptosis-Related Genes CDK1 and COA6 Involved in the Prognosis Prediction of Liver Hepatocellular Carcinoma.

Background: Liver hepatocellular carcinoma (LIHC) is the most frequently seen type of primary liver cancer. Cuproptosis is a novel form of cell death highly associated with mitochondrial metabolism. However, the clinical impact and pertinent mechanism of cuproptosis genes in LIHC remain largely unknown. Methods: From public databases, we systematically assessed common genes from LIHC differentially expressed genes (DEGs) and cuproptosis-related genes using bioinformatics analysis. These common genes were then analyzed by enrichment analysis, mutation analysis, risk score model, and others to find candidate hub genes related to LIHC and cuproptosis. Next, hub genes were determined by expression, clinical factors, immunoassay, and prognostic nomogram. Results: Based on 129 cuproptosis-related genes and 3492 LIHC DEGs, we totally identified 21 downregulated and 18 upregulated common genes, and they were enriched in pathways, such as zinc ion homeostasis and oxidative phosphorylation. In the mutation analysis, missense mutation was the most common type in LIHC patients, and the common gene F5 had the highest mutation frequency. After LASSO-Cox regression analysis and prognostic analysis, CDK1, ABCB6, LCAT, and COA6 were identified as prognostic signature genes. Among them, ABCB6 and LCAT were lowly expressed in tumors, and CDK1 and COA6 were highly expressed in tumors. In addition, ABCB6 and LCAT were negatively correlated with 6 kinds of immune cells, while CDK1 and COA6 were positively correlated with them. CDK1 and COA6 were identified as hub genes related to LIHC by Cox regression analysis and prognostic nomogram. Conclusion: CDK1 and COA6 are two oncogenes in LIHC, which are involved in the molecular mechanism of cuproptosis and LIHC. Besides, CDK1 and COA6 can positively regulate the expressions of immune cells in LIHC. In clinical practice, they can be used as immunotherapeutic targets and prognostic predictors in LIHC, which sheds new light on the scientific fields of cuproptosis and LIHC.

Tumor suppression by RNA surveillance.

A cyclin-dependent kinase triggers degradation of prematurely terminated RNAs.

Oncogenic CDK13 mutations impede nuclear RNA surveillance.

RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 (CDK13) is mutated in melanoma, and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We found recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor-suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.