The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling

Zhang, Huan-Tian; Gui, Tao; Sang, Yuan; Yang, Jie; Li, Yu-Hang; Liang, Guihong; Li, Thomas; He, Qing‐Yu; Zha, Zhengang

doi:10.1002/jcb.25863

Cited by 47 publications

(47 citation statements)

References 35 publications

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“…13 Moreover, the high expression of YAP in neuroblastoma is correlated with tumour grade of neuroblastoma. 13 Consistent with these studies, our results showed that YAP was abundantly expressed in different glioma cell lines, and the expres- There are evidences revealing that YAP can modulate tumour cell proliferation through regulating the expression of cell cycle proteins, such as p27 Kip1 , p21 45 and cyclinD1. 25,28,43 p27 Kip1 is a cyclin-dependent kinases inhibitor that involved in the pathogenesis of neuroblastoma.…”

Section: Discussionsupporting

confidence: 88%

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27^Kip1 mediated by Akt

Shen

Xie

et al. 2019

Cell Proliferation

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Objective We aimed to investigate the roles and underlying mechanisms of YAP in the proliferation of neuroblastoma cells. Methods The expression level of YAP was evaluated by Western blotting and immunocytochemistry. Cell viability, cell proliferation and growth were detected by CCK‐8, PH3 and Ki67 immunostaining, and the real‐time cell analyser system. The nuclear and cytoplasmic proteins of p27Kip1 were dissociated by the nuclear‐cytosol extraction kit and were detected by Western blotting and immunocytochemistry. mRNA levels of Akt, CDK5 and CRM1 were determined by qRT‐PCR. Results YAP was enriched in SH‐SY5Y cells (a human neuroblastoma cell line). Knock‐down of YAP in SH‐SY5Y cells or SK‐N‐SH cell line (another human neuroblastoma cell line) significantly decreased cell viability, inhibited cell proliferation and growth. Mechanistically, knock‐down of YAP increased the nuclear location of p27Kip1, whereas serum‐induced YAP activation decreased the nuclear location of p27Kip1 and was required for cell proliferation. Meanwhile, overexpression of YAP in these serum‐starved SH‐SY5Y cells decreased the nuclear location of p27Kip1, promoted cell proliferation and overexpression of p27Kip1 in YAP‐activated cells inhibited cell proliferation. Furthermore, knock‐down of YAP reduced Akt mRNA and protein levels. Overexpression of Akt in YAP‐downregulated cells decreased the nuclear location of p27Kip1 and accelerated the proliferation of SH‐SY5Y cells. Conclusions Our studies suggest that YAP promotes the proliferation of neuroblastoma cells through negatively controlling the nuclear location of p27Kip1 mediated by Akt.

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Section: Discussionsupporting

confidence: 88%

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27^Kip1 mediated by Akt

Shen

Xie

et al. 2019

Cell Proliferation

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“…Similarly, lovastatin was reported to reduce the survival of Ewing sarcoma cells [260]. Among epigenetic drugs, only JQ1 was previously reported to affect LATS1, YAP and TAZ in chondrosarcoma [182], potentially by restoring suppressed AMOT expression [183] (Figure 4). Among natural compounds, agave extract was reported to downregulate YAP and TAZ mRNA and the protein in osteosarcoma cell lines by a mechanism that still needs to be explored [261].…”

Section: Resultsmentioning

confidence: 94%

“…A recent study identified YAP nuclear accumulation as a consequence of LATS1 inactivation by protein arginine methyltransferase 1 (PRMT1) as an independent bad prognostic factor in chondrosarcoma [181]. Finally, the treatment of chondrosarcoma cells with the BET-bromodomain inhibitor JQ1 downregulated YAP/TAZ and LATS1, leading to the upregulation of cyclin-dependent kinase inhibitor 1a (CDKN1A/p21) and cell cycle arrest, senescence and apoptosis [182]. Potentially, this downregulation was mediated by epigenetic restoration of the expression of the inhibitory YAP/TAZ-binding scaffold protein angiomotin (AMOT) [183].…”

Section: Yap/taz In Chondrosarcomamentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

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“…Different concentrations of 17‐AAG (0.05, 0.5, 1, 10, and 50 µM) were added to the cells and incubated for the indicated times. Afterwards, cell counting kit‐8 (CCK‐8, C0038, Beyotime, China) was used to determine the cell viability according to manufacturer's instructions with minor modifications …”

Section: Methodsmentioning

confidence: 99%

Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK‐3β/β‐catenin signaling

Liang

Liu

et al. 2017

J of Cellular Biochemistry

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Osteosarcoma (OS) is the most malignant primary bone tumor in children and adolescents with limited treatment options and poor prognosis. Recently, aberrant expression of Runx2 has been found in OS, thereby contributing to the development, and progression of OS. However, the upstream signaling molecules that regulate its expression in OS remain largely unknown. In the present study, we first confirmed that the inhibition of HSP90 with 17-AAG caused significant apoptosis of OS cells via a caspase-3-dependent mechanism, and that inhibition or knockdown of HSP90 by 17-AAG or siRNAs significantly suppressed mRNA and protein expression of Runx2. Furthermore, we provided evidence that Runx2 was transcriptionally regulated by HSP90 when using MG132 and CHX chase assay. We also demonstrated that β-catenin was overexpressed in OS tissue, and that knockdown of β-catenin induced pronounced apoptosis of OS cells in the presence or absence of 17-AAG.Interestingly, this phenomenon was accompanied with a significant reduction of Runx2 and Cyclin D1 expression, indicating an essential role of Runx2/Cyclin D1 in 17-AAG-induced cells apoptosis. Moreover, we demonstrated that the apoptosis of OS cells induced by 17-AAG did require the involvement of the AKT/GSK-3β/ β-catenin signaling pathway by using pharmacological inhibitor GSK-3β (LiCl) or siGSK-3β. Our findings reveal a novel mechanism that Runx2 is transcriptionally

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The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling

Cited by 47 publications

References 35 publications

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27^Kip1 mediated by Akt

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27^Kip1 mediated by Akt

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK‐3β/β‐catenin signaling

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The BET Bromodomain Inhibitor JQ1 Suppresses Chondrosarcoma Cell Growth via Regulation of YAP/p21/c-Myc Signaling

Cited by 47 publications

References 35 publications

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27Kip1 mediated by Akt

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27Kip1 mediated by Akt

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK‐3β/β‐catenin signaling

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YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27^Kip1 mediated by Akt

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27^Kip1 mediated by Akt