Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer

Becker, Finn; Joerg, Vincent; Hupe, Marie C.; Roth, Doris; Krupar, Rosemarie; Lubczyk, Verena; Kuefer, Rainer; Sailer, Verena; Duensing, Stefan; Kirfel, Jutta; Merseburger, Axel S.; Brägelmann, Johannes; Perner, S.; Offermann, Anne

doi:10.1002/ijc.32551

Cited by 31 publications

(18 citation statements)

References 48 publications

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“…The expression of all three replicates per sample was considered, and highest expression in a single core was used for further analysis in cases of heterogeneous staining levels. Androgen receptor (AR) expression was detected and evaluated as described before (Becker et al, 2020).…”

Section: Immunohistochemistrymentioning

confidence: 99%

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Gorodetska

Offermann

Pueschel

et al. 2021

Preprint

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Cancer stem cells (CSC) are characterized by high self-renewal capacity, tumor-initiating potential, and therapy resistance. Aldehyde dehydrogenase (ALDH)+ cell population serves as an indicator of prostate CSCs with increased therapy resistance, enhanced DNA double-strand break repair, and activated epithelial-mesenchymal transition (EMT) and migration. Numerous ALDH genes contribute to ALDH enzymatic activity; however, only some of them showed clinical relevance. We found that ALDH1A1 and ALDH1A3 genes functionally regulate CSC properties and radiation sensitivity of PCa. We revealed a negative correlation between ALDH1A1 and ALDH1A3 expression in publicly available prostate cancer (PCa) datasets and demonstrated that ALDH1A1 and ALDH1A3 have opposing predictive value for biochemical recurrence-free survival. Our data suggest an association of ALDH1A1 with the metastatic burden, elucidating the role of ALDH genes in the metastatic spread and homing to the bone, which can be, at least partially, attributed to regulating the transforming growth factor beta 1 (TGFB1) and matrix metalloproteinases (MMPs). ALDH genes play a diverse role in PCa development under AR and β-catenin-dependent regulation, with ALDH1A1 becoming dominant in later stages of tumor development when PCa cells gain androgen independence. Taken together, our results indicate that ALDH1A1 and ALDH1A3 modulate PCa radiosensitivity, regulate CSCs phenotype, and spread of PCa cells to the bone, therefore having clinical implication for identifying patients at high risk for progression to metastatic disease.

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Section: Immunohistochemistrymentioning

confidence: 99%

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Gorodetska

Offermann

Pueschel

et al. 2021

Preprint

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“…A series of phenotypic functional experiments demonstrated that CDK19 may participate in HCC development by promoting proliferation, migration and invasion. These phenotypic characteristics are similar to those of CDK19 in prostate cancer, gastric cancer, and head and neck squamous cell carcinoma [ 48 – 50 ]. Above all, CDK19 is an oncogene and plays an important role in the pathology of HCC.…”

Section: Discussionmentioning

confidence: 75%

Cyclin-dependent kinase 19 upregulation correlates with an unfavorable prognosis in hepatocellular carcinoma

et al. 2021

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Objectives Cyclin-dependent kinase 19 (CDK19) is a component of the mediator coactivator complex, which is required for transcriptional activation. In this study, we utilized public databases and wet-bench hepatic cell line experiments to elucidate the potential roles of CDK19 in hepatocellular cancer (HCC). Materials and methods We studied the relationships between CDK19 expression and several clinical features related to HCC via the Oncomine and UALCAN databases. The prognostic value of CDK19 was tested using the Kaplan–Meier Plotter database. We presented the mutations of CDK19 and addressed the relation of CDK19 expression with immune cell infiltration by means of the cBioPortal, Catalogue of Somatic Mutations in Cancer (COSMIC) and Tumor IMmune Estimation Resource (TIMER) databases. Hub genes were obtained and further analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. To test the in silico findings, we knocked down CDK19 with short hairpin RNA (shRNA) technology in two hepatic cell lines and conducted several functional characterization experiments. Results Marked CDK19 upregulation was found in HCC tissues versus normal liver tissues, and CDK19 mRNA expression had high diagnostic value in HCC patients. Subgroup analysis showed that CDK19 overexpression was associated with sex, tumor stage and TP53 mutation status. The prognostic value of CDK19 upregulation for overall survival (OS) was significant in patients with stage 2–3, stage 3–4, and grade 2 disease. One percent of the patients had CDK19 mutations, but no relationship between CDK19 mutation and prognosis was observed. CDK19 was positively correlated with the abundances of CD4 + T cells, macrophages and dendritic cells. We identified 10 genes correlated with CDK19, 8 of which presented excellent prognostic value in HCC. These hub genes were directly involved in cell division and regulation of the G2/M cell cycle transition. Protein–protein interaction (PPI) and pathway predictions indicated that CDK19 is highly likely to be involved in several cellular functions, such as proliferation, migration, and invasion. These functions were strongly interfered from two independent hepatic cell lines after CDK19 knockdown. Conclusions CDK19 could be a prognostic marker in HCC, and its therapeutic potential in HCC needs further study.

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“…The prevalence of an AR low/negative expression pattern has generally been underappreciated, but has been observed in a number of experiments ( Table 2 ). [4] , [5] , [7] , [8] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] , [89] More generally, several studies have observed decreased AR protein expression/intensity in hormone-refractory patient metastases, 90 and in hormone-refractory patients when compared to normal, primary, or hormone-sensitive tissue. [86] , [91] CRPC subtypes that exhibit AR low/negative expression patterns (e.g.…”

Section: Resultsmentioning

confidence: 99%

Development and prevalence of castration-resistant prostate cancer subtypes

Vellky

Ricke

2020

Neoplasia

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Background Castration-resistant prostate cancer (CRPC) occurs when prostate cancer (CaP) progresses under therapy-induced castrate conditions. Several mechanisms have been proposed to explain this acquired resistance, many of which are driven by androgen receptor (AR). Recent findings, however, sub-classified CRPC by downregulation/absence of AR in certain subtypes that consequently do not respond to anti-androgen therapies. To highlight the significance of CRPC sub-classification, we reviewed the development and treatment of CRPC, AR downregulation in CRPC, and summarized recent reports on the prevalence of CRPC subtypes. Methods Using a medline-based literature search, we reviewed mechanisms of CRPC development, current treatment schemes, and assessed the prevalence of AR low/negative subtypes of CRPC. Additionally, we performed immunohistochemical staining on human CRPC specimens to quantify AR expression across CRPC subtypes. Results In the majority of cases, CRPC continues to rely on AR signaling, which can be augmented in castrate-conditions through a variety of mechanisms. However, recently low/negative AR expression patterns were identified in a significant proportion of patient samples from a multitude of independent studies. In these AR low/negative cases, we postulated that AR protein may be downregulated by (1) promoter methylation, (2) transcriptional regulation, (3) post-transcriptional regulation by microRNA or RNA-binding-proteins, or (4) post-translational ubiquitination-mediated degradation. Conclusions Here, we discussed mechanisms of CRPC development and summarized the overall prevalence of CRPC subtypes; interestingly, AR low/negative CRPC represented a considerable proportion of diagnoses. Because these subtypes cannot be effectively treated with AR-targeted therapeutics, a better understanding of AR low/negative subtypes could lead to better treatment strategies and increased survival.

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Increased mediator complex subunit CDK19 expression associates with aggressive prostate cancer

Cited by 31 publications

References 48 publications

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Cyclin-dependent kinase 19 upregulation correlates with an unfavorable prognosis in hepatocellular carcinoma

Development and prevalence of castration-resistant prostate cancer subtypes

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