In cells, signal transduction heavily relies on the intricate regulation of protein kinases, which provide the fundamental framework for modulating most signaling pathways. Dysregulation of kinase activity has been implicated in numerous pathological conditions, particularly in cancer. The druggable nature of most kinases positions them into a focal point during the process of drug development. However, a significant challenge persists, as the role and biological function of nearly one third of human kinases remains largely unknown.Within this diverse landscape, cyclin-dependent kinases (CDKs) emerge as an intriguing molecular subgroup. In human, this kinase family encompasses 21 members, involved in several key biological processes. Remarkably, 13 of these CDKs belong to the category of understudied kinases, and only 5 having undergone broad investigation to date. This knowledge gap underscores the pressing need to delve into the study of these kinases, starting with a comprehensive review of the less-explored ones.Here, we will focus on the PCTAIRE subfamily of CDKs, which includes CDK16, CDK17, and CDK18, arguably among the most understudied CDKs members. To contextualize PCTAIREs within the spectrum of human pathophysiology, we conducted an exhaustive review of the existing literature and examined available databases. This approach resulted in an articulate depiction of these PCTAIREs, encompassing their expression patterns, 3D configurations, mechanisms of activation, and potential functions in normal tissues and in cancer.We propose that this effort offers the possibility of identifying promising areas of future research that extend from basic research to potential clinical and therapeutic applications.

Cyclin-Dependent Kinase 16 (CDK16) plays significant biological roles in various diseases. Nonetheless, its function in different cancer types and its relationship with the Tumor Immune Microenvironment (TIME) are still not well-understood.
We analyzed the expression profile, genetic alterations, clinical features, and prognostic value of CDK16 in pan-cancer using data from The Cancer Genome Atlas, Genotype-Tissue Expression databases, and in vitro experiments. Additionally, the TIMER2 and ImmuCellAI databases were utilized to assess the correlation between CDK16 expression and immune cell infiltration levels. Finally, we examined the correlation between CDK16 and the response to immunotherapy using collected immunotherapy data.
CDK16 is notably overexpressed in pan-cancer and is a risk factor for poor prognosis in various cancers. Our findings reveal that CDK16 regulates not only cell cycle-related functions to promote cell proliferation but also the autoimmunity-related functions of the innate and adaptive immune systems, along with other immune-related signaling pathways. Moreover, CDK16 overexpression contributes to an immunosuppressive tumor microenvironment, extensively suppressing immune-related features such as the expression of immune-related genes and pathways, as well as the count of immune-infiltrating cells. Our analysis indicated that individuals with low CDK16 expression showed higher response rates to immune checkpoint inhibitors and longer overall survival compared to those with high CDK16 expression.
This study establishes CDK16 as a potential biomarker for predicting poor prognosis in a wide range of cancers. Its role in shaping the immunosuppressive tumor microenvironment and influencing the efficacy of immunotherapy highlights the urgent need for developing targeted therapies against CDK16, offering new avenues for cancer treatment and management.

Cyclin-dependent kinases (CDKs) play an important role in cell division. Given that abnormal cell proliferation caused by dysregulation of cell division is one of the major causes of endometrial cancer (EC), it is important to elucidate the role of CDK family genes in the diagnosis and prognosis of EC. In this study, The Cancer Genome Atlas (TCGA) database was used to analyze the frequency of copy number variations and somatic mutations in 26 CDK family genes. Subsequently, the expression of these genes in EC was assessed, and their relationship with overall survival (OS) was examined via Kaplan-Meier analysis to assess their prognostic significance. A prognostic model based on seven CDK genes was constructed using Lasso and Cox regression, and the predictive performance of the model was analyzed using Kaplan-Meier analysis and column line plots. The correlation between CDK genes and immune cells was also examined. Patients with EC in the high-risk group had a poorer prognosis. The results of qRT-PCR and immunohistochemical analyses validated that CDK16 is highly expressed in EC tissues. Patients with EC with high CDK16 expression had worse 10-year OS than patients with low CDK16 expression. These findings suggest that the prognostic model constructed based on CDK genes can help to develop individualized and targeted treatment strategies for patients with EC.

OBJECTIVE: LncRNA HCG18 has been reported to act as a tumor promoter in gastric cancer, hepatocellular carcinoma and nasopharyngeal carcinoma. However, the role of HCG18 in melanoma is still not clear. In this study, we detected the expression and molecular function of HCG18 in melanoma.
METHODS: The expression of HCG18 in melanoma cell lines and 50 pairs of melanoma and corresponding non-cancer tissues was detected by RT-qPCR. The relationship between HCG18 and clinicopathology was analyzed. We used HCG18 overexpressing melanoma cell lines A375 and M14, and si-HCG18 to knock down HCG18 expression. CCK-8, clone formation, Transwell assay and FCM were used to explore the effect of HCG18 knockdown on cell proliferation, migration, invasion and apoptosis in melanoma cells. Bioinformatics software was used to predict the downstream miRNA regulated by HCG18, and the downstream target genes regulated by miR-324-5p. Dual-luciferase reporter assay and RNA pull-down assay were used to verify whether miR-324-5p was related to the predicted sequence of HCG18.
RESULTS: HCG18 was highly expressed in melanoma tissues and cells. Besides, we found that HCG18 was closely correlated with thickness, TNM stage and metastasis. Functional experiments discovered that HCG18 knockdown restrained cell proliferation, migration and invasion, while promoted cell apoptosis in melanoma cells. HCG18 was confirmed to be a sponge of miR-324-5p, and CDK16 might be a downstream gene of miR-324-5p. HCG18 was found to reverse the effect of miR-324-5p by upregulating CDK16 expression in melanoma cell proliferation, apoptosis, migration and invasion in vitro.
CONCLUSIONS: This study indicated that HCG18 played an essential role in the pathogenesis of melanoma and suggested that HCG18 might be a potential target for the treatment and diagnosis of melanoma.

PCTAIRE1 (also known as CDK16) is a serine-threonine kinase implicated in physiological processes like neuronal development, vesicle trafficking, spermatogenesis and cell proliferation. However, its exact role in cell division remains unclear. In this study, using a library screening approach, we identified PCTAIRE1 among several candidates that resisted mitotic arrest and mitotic cell death induced by polyomavirus small T (PolST) expression in mammalian cells. Our study showed that PCTAIRE1 is a mitotic kinase that localizes at centrosomes during G2 and at spindle poles as the cells enter mitosis, and then at the midbody during cytokinesis. We also report that PCTAIRE1 protein levels fluctuate through the cell cycle and reach their peak at mitosis, during which there is an increase in PCTAIRE1 phosphorylation as well. Interestingly, knockdown of PCTAIRE1 resulted in aberrant mitosis by interfering with spindle assembly and chromosome segregation. Further, we found that PCTAIRE1 promotes resistance of cancer cells to antimitotic drugs, and this underscores the significance of PCTAIRE1 as a potential drug target for overcoming chemotherapeutic resistance. Taken together, these studies establish PCTAIRE1 as a critical mediator of mitotic progression and highlight its role in chemotherapeutic resistance. This article has an associated First Person interview with the first author of the paper.

Long non-coding RNAs (lncRNAs) are associated with the healing of burn wounds in the dermis. The present study aimed to probe the role and regulatory network of the lncRNA TPT1 antisense RNA 1 (TPT1-AS1) in human dermal fibroblasts (HDFs) following thermal injury. A model of thermally injured cells was constructed with HDFs. The levels of TPT1-AS1, microRNA (miR)-324-5p and cyclin-dependent kinase (CDK)16 were determined through reverse transcription-quantitative PCR. Cell viability, cell cycle distribution, cell apoptosis rate and extracellular matrix (ECM) synthesis were assessed with a series of in vitro gain-of-function experiments and MTT, flow cytometry and western blot analyses. The binding ability of miR-324-5p and TPT1-AS1 (or the 3\' untranslated region of CDK16) was identified via bioinformatics analysis and luciferase reporter assay. It was found that TPT1-AS1 and CDK16 were downregulated, but miR-324-5p was upregulated, in the HDFs after thermal injury. TPT1-AS1 elevation induced cell viability and ECM synthesis but attenuated cell cycle arrest at the G0/G1 stage and decreased the cell apoptosis rate of thermally injured HDFs. In addition, TPT1-AS1 sponged miR-324-5p to modulate CDK16 expression. Moreover, silencing CDK16 weakened the impacts of TPT1-AS1 upregulation on cell function and ECM synthesis in heat-treated HDFs. In summary, TPT1-AS1 relieved cell injury and induced ECM synthesis by sponging miR-324-5p and targeting CDK16 in the HDFs after thermal injury, implying a protective role for TPT1-AS1 in the burn wound healing process.

OBJECTIVE: (1E,4E)-1,5-bis(2-bromophenyl) penta-1,4-dien-3-one (GL63) is a curcumin analog that can protect against carcinogenesis in hepatocellular carcinoma (HCC). The aim of this study was to explore the molecular mechanism of GL63 in HCC.
METHODS: Cell viability was examined by cell counting kit-8 (CCK-8) assay. Circular RNA zinc finger protein 83 (circZNF83), microRNA-324-5p (miR-324-5p), and cyclin-dependent kinase 16 (CDK16) levels were measured via the quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was assessed using colony formation assay. Flow cytometry was performed for detecting cell cycle and apoptosis. Protein analysis was conducted by western blot. Cell migration and invasion were determined using transwell assay. Target relation was analyzed using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The function of GL63 in vivo was researched by xenograft model in mice.
RESULTS: GL63 inhibited the circZNF83 expression in HCC cells. CircZNF83 overexpression attenuated the inhibitory effects of GL63 on HCC cell growth, cell cycle progression, migration, and invasion but the promoting effect on cell apoptosis. CircZNF83 served as a sponge of miR-324-5p and circZNF83/miR-324-5p axis was involved in the functional regulation of GL63 in HCC progression. Moreover, CDK16 was a downstream target of miR-324-5p and circZNF83 could regulate the CDK16 expression by sponging miR-324-5p. The anti-tumor function of GL63 was also related to the miR-324-5p/CDK16 axis. In addition, GL63 inactivated the JAK2/STAT3 pathway via downregulating circZNF83 to mediate the miR-324-5p/CDK16 axis. GL63 also repressed tumor growth in vivo through the circZNF83/miR-324-5p/CDK16-mediated JAK2/STAT3 signal inhibition.
CONCLUSIONS: This study suggested GL63 impeded the HCC development by blocking the JAK2/STAT3 signaling pathway via mediating the circZNF83/miR-324-5p/CDK16 axis.

Circular RNAs (circRNAs) have been demonstrated to play important roles in cancer progress. However, the roles in hepatocellular carcinoma (HCC) are still unclear. Here, we found has_circRNA_001306 (circ_1306) was up-regulated in HCC tissues and cell lines. Knockdown the expression circ_1306 significantly suppressed HCC cell proliferation and induced the cell apoptosis in vitro and in vivo. Furthermore, we identified circ_1306 could up-regulate the expression of CDK16 by sponging miR-584-5p. The expression of miR-584-5p was decreased, and the expression of CDK16 was increased in HCC tissues and cell lines. Meanwhile, either knockdown of miR-584-5p or overexpression of CDK16 could suppress the HCC cell proliferation. In vivo, overexpression of miR-584-5p or knockdown of circ_1306 could inhibit the expression of CDK16, and suppress tumour growth. Altogether, our findings suggested that circ_1306 could promoter HCC progress by miR-584-5p/CDK16 axis, which provided a novel marker for HCC diagnosis and treatment.

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AMPK is one of the main regulators of energy homeostasis in the cell, achieving this role in part by upregulating autophagy in times of nutrient deprivation. Previous reports have described several AMPK substrates involved in autophagy regulation; however, there are still undiscovered AMPK downstream effectors that could play an important role in autophagy. In a new article, Dohmen et al. discovered that the CCNY-CDK16 complex is a novel AMPK substrate involved in autophagy activation.