Skp2–MacroH2A1–CDK8 axis orchestrates G2/M transition and tumorigenesis

Xu, Dazhi; Li, Chien‐Feng; Zhang, Xian; Gong, Zhaohui; Chan, Chia‐Hsin; Lee, Szu Wei; Jin, Guoxiang; Rezaeian, Abdol Hossein; Han, Fei; Wang, Jing; Yang, Wei; Feng, Zizhen; Chen, Wei; Wu, Ching Yuan; Wang, Ying Jan; Chow, Lu-Ping; Zhu, Xiao Feng; Zeng, Yi Xin; Lin, Hui Kuan

doi:10.1038/ncomms7641

Cited by 92 publications

(91 citation statements)

References 37 publications

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“…Indeed, Xu et al . [22] very recently reported that CDK8 is implicated in breast carcinogenesis and that the expression of CDK8 protein (or, more precisely, CDK8/19, since these authors used the same cross-reactive antibody as in our study) is positively correlated with tumor status, nodal metastasis and stage in breast cancer. CDK8 gene expression was found to be elevated by Skp2 SCF complex that promotes the ubiquitination and degradation of histone variant macroH2A, a negative regulator of CDK8 expression [15].…”

Section: Immunohistochemical Analysis Of Cdk8/19 Protein Expression Imentioning

confidence: 60%

“…CDK8 gene expression was found to be elevated by Skp2 SCF complex that promotes the ubiquitination and degradation of histone variant macroH2A, a negative regulator of CDK8 expression [15]. The oncogenic role of CDK8 in breast cancer was suggested to be due to CDK8 facilitating the degradation of cell cycle inhibitor p27 [22]. …”

Section: Immunohistochemical Analysis Of Cdk8/19 Protein Expression Imentioning

confidence: 99%

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Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

Broude

Győrffy²,

Chumanevich³

et al. 2015

CCDT

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CDK8 and its paralog CDK19, in complex with CCNC, MED12 and MED13, are transcriptional regulators that mediate several carcinogenic pathways and the chemotherapy-induced tumor-supporting paracrine network. Following up on our previous observation that CDK8, CDK19 and CCNC RNA expression is associated with shorter relapse-free survival (RFS) in breast cancer, we now found by immunohistochemical analysis that CDK8/19 protein is overexpressed in invasive ductal carcinomas relative to non-malignant mammary tissues. Meta-analysis of transcriptomic data revealed that higher CDK8 expression is associated with shorter RFS in all molecular subtypes of breast cancer. These correlations were much stronger in patients who underwent systemic adjuvant therapy, suggesting that CDK8 impacts the failure of systemic therapy. The same associations were found for CDK19, CCNC and MED13. In contrast, MED12 showed the opposite association with a longer RFS. The expression levels of CDK8 in breast cancer samples were directly correlated with the expression of MYC, as well as CDK19, CCNC and MED13 but inversely correlated with MED12. CDK8, CDK19 and CCNC expression was strongly increased and MED12 expression was decreased in tumors with mutant p53. Gene amplification is the most frequent type of genetic alterations of CDK8, CDK19, CCNC and MED13 in breast cancers (9.7% of which have amplified MED13), whereas point mutations are more common in MED12. These results suggest that the expression of CDK8 and its interactive genes has a profound impact on the response to adjuvant therapy in breast cancer in accordance with the role of CDK8 in chemotherapy-induced tumor-supporting paracrine activities.

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Section: Immunohistochemical Analysis Of Cdk8/19 Protein Expression Imentioning

confidence: 60%

Section: Immunohistochemical Analysis Of Cdk8/19 Protein Expression Imentioning

confidence: 99%

Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

Broude

Győrffy²,

Chumanevich³

et al. 2015

CCDT

View full text Add to dashboard Cite

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“…Various studies have discovered that Skp2 plays an important role in tumorigenesis in a variety of human types of cancer (40,41). However, the function of Skp2 in OS remains largely obscure.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Ding

Han

et al. 2017

Oncology Reports

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Abstract. Osteosarcoma (OS) is a common bone tumor that mainly affects children and young adults. S-phase kinase-associated protein 2 (Skp2) has been characterized to play a critical oncogenic role in a variety of human malignancies. However, the biological function of Skp2 in OS remains largely obscure. In the present study, we elucidated the role of Skp2 in cell growth, cell cycle, apoptosis and migration in OS cells. We found that depletion of Skp2 inhibited cell growth in both MG-63 and SW 1353 cells. Moreover, we observed that depletion of Skp2 triggered cell apoptosis in two OS cell lines. Furthermore, downregulation of Skp2 induced cell cycle arrest in the G0/G1 phase in OS cells. Notably, our wound healing assay results revealed that inhibition of Skp2 suppressed cell migration in OS cells. Invariably, our western blot results demonstrated that depletion of Skp2 in OS cells inhibited activation of pAkt and increased p27 expression in OS cells, suggesting that Skp2 exerted its oncogenic function partly through the regulation of Akt and p27. Our findings revealed that targeting Skp2 could be a promising therapeutic strategy for the treatment of OS.

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“…CDK8/19 regulation is especially pertinent in cancers, where CDK8 positively regulates several cancer-relevant signaling pathways (5), including Wnt/β-catenin (9), the serum response network (6), TGFβ (10), HIF1α (7), and estrogen receptor (8). CDK8 has been identified as an oncogene implicated in colorectal (9), pancreatic (11), and breast (3,8,12,13) cancers and melanomas (14) and associated with the stem cell phenotype (15). CDK8/19 inhibition also has an antiproliferative effect in a subset of leukemias (16,17).…”

Section: Significancementioning

confidence: 99%

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

Chen

Liang

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

130

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The nuclear factor-κB (NFκB) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NFκB show significant side effects, possibly due to sustained NFκB suppression. Drugs affecting induced, but not basal, NFκB activity may have the potential to provide therapeutic benefit without associated toxicity. NFκB activation by stress-inducible cell cycle inhibitor p21 was shown to be mediated by a p21-stimulated transcription-regulating kinase CDK8. CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer; CDK8/19 inhibitors are entering clinical development. Here we show that CDK8/19 inhibition by different small-molecule kinase inhibitors or shRNAs suppresses the elongation of NFκB-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNFα. On NFκB activation, CDK8/19 are corecruited with NFκB to the promoters of the responsive genes. Inhibition of CDK8/19 kinase activity suppresses the RNA polymerase II C-terminal domain phosphorylation required for transcriptional elongation, in a gene-specific manner. Genes coregulated by CDK8/19 and NFκB includeIL8,CXCL1, andCXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NFκB-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NFκB-regulated genes or promoters; the same selective regulation of newly induced transcription was observed with other transcription signals potentiated by CDK8/19. This selective role of CDK8/19 identifies these kinases as mediators of transcriptional reprogramming, a key aspect of development and differentiation as well as pathological processes.

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Skp2–MacroH2A1–CDK8 axis orchestrates G2/M transition and tumorigenesis

Cited by 92 publications

References 37 publications

Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

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