A RUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells

Shin, Min Hwa; He, Yunlong; Marrogi, Eryney; Piperdi, Sajida; Ren, Ling; Khanna, Chand; Görlick, Richard; Liu, Chengyu; Huang, Jing

doi:10.1371/journal.pgen.1005884

Cited by 37 publications

(48 citation statements)

References 39 publications

(57 reference statements)

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“…Interestingly, the p53 cellular protein acts as a negative regulator of osteoblastogenesis under normal conditions, repressing transcription factor such as Osterix and Runx2 (11), which are required in the initial osteogenesis phase in osteoprogenitor cells (12,13). However, Runx2 may act by inhibiting the function of p53 in activating apoptosis by inducing c-MYC transcription by histone modifications (14). This explains the highly elevated Runx2 expression levels in OS cells.…”

Section: Introductionmentioning

confidence: 99%

Biology and pathogenesis of human osteosarcoma (Review)

Azevedo¹,

Fernandes

et al. 2019

Oncol Lett

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Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or apoptosis control during osteogenesis, allowing the survival of cells which have undergone alterations during differentiation. Epigenetic events, including DNA methylation, histone modifications, nucleosome remodeling and expression of non-coding RNAs have been identified as possible risk factors for the tumor. It has been reported that p53 target genes or those genes that have their activity modulated by p53, in addition to other tumor suppressor genes, are silenced in OS-derived cell lines by hypermethylation of their promoters. In osteogenesis, osteoblasts are formed from pluripotent mesenchymal cells, with potential for self-renewal, proliferation and differentiation into various cell types. This involves complex signaling pathways and multiple factors. Any disturbance in this process can cause deregulation of the differentiation and proliferation of these cells, leading to the malignant phenotype. Therefore, the origin of OS seems to be multifactorial, involving the deregulation of differentiation of mesenchymal cells and tumor suppressor genes, activation of oncogenes, epigenetic events and the production of cytokines. Contents 1. Introduction 2. Biology of human OS 3. Role of differentiation of mesenchymal stem cells 4. Role of DNA changes 5. Role of deregulating the expression of tumor suppressor genes 6. Regulation of oncogene expression 7. Role of epigenetic mechanisms 8. Role of non-coding RNAs 9. Role of cytokines 10. Conclusion

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Section: Introductionmentioning

confidence: 99%

Biology and pathogenesis of human osteosarcoma (Review)

Azevedo¹,

Fernandes

et al. 2019

Oncol Lett

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“…This growth inhibition was associated with reduced interactions between CBFβ and RUNX1, reduced RUNX1 occupancy on target genes and altered gene expression . Furthermore, Shin et al recently demonstrated that knockdown of RUNX2 or CBFβ induces apoptosis in some human OS cell lines, and identified potential downstream effectors responsible for this activity, including MYC . Another recent study identified tumour suppressive activity of a microRNA through its targeting of RUNX2 in OS cells .…”

Section: Discussionmentioning

confidence: 97%

“…37 Furthermore, Shin et al recently demonstrated that knockdown of RUNX2 or CBFβ induces apoptosis in some human OS cell lines, and identified potential downstream effectors responsible for this activity, including MYC. 38 Another recent study identified tumour suppressive activity of a microRNA through its targeting of RUNX2 in OS cells. 39 Thus, in this study, we aimed to identify whether inhibiting the interaction between RUNX2 and CBFβ, using allosteric inhibitors of CBFβ, would be sufficient to induce antitumour effects in canine OSA cell lines or if this activity may require knockdown of RUNX2 levels.…”

Section: Discussionmentioning

confidence: 99%

The interaction between RUNX2 and core binding factor beta as a potential therapeutic target in canine osteosarcoma

Alegre

Ormonde

Godinez

et al. 2019

Vet Comparative Oncology

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Osteosarcoma remains the most common primary bone tumour in dogs with half of affected dogs unable to survive 1 year beyond diagnosis. New therapeutic options are needed to improve outcomes for this disease. Recent investigations into potential therapeutic targets have focused on cell surface molecules with little clear therapeutic benefit. Transcription factors and protein interactions represent underdeveloped areas of therapeutic drug development. We have utilized allosteric inhibitors of the core binding factor transcriptional complex, comprised of core binding factor beta (CBFβ) and RUNX2, in four canine osteosarcoma cell lines Active inhibitor compounds demonstrate anti‐tumour activities with concentrations demonstrated to be achievable in vivo while an inactive, structural analogue has no activity. We show that CBFβ inhibitors are capable of inducing apoptosis, inhibiting clonogenic cell growth, altering cell cycle progression and impeding migration and invasion in a cell line‐dependent manner. These effects coincide with a reduced interaction between RUNX2 and CBFβ and alterations in expression of RUNX2 target genes. We also show that addition of CBFβ inhibitors to the commonly used cytotoxic chemotherapeutic drugs doxorubicin and carboplatin leads to additive and/or synergistic anti‐proliferative effects in canine osteosarcoma cell lines. Taken together, we have identified the interaction between components of the core binding factor transcriptional complex, RUNX2 and CBFβ, as a potential novel therapeutic target in canine osteosarcoma and provide justification for further investigations into the anti‐tumour activities we describe here.

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“…For ChIP-seq, we followed our previous procedures without major modifications (He et al., 2015, Li et al., 2012, Shin et al., 2016). Pathway analyses using DAVID Bioinformatics Resources were previously described (Huang da et al., 2009, Lee et al., 2010).…”

Section: Methodsmentioning

confidence: 99%

cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma

Zhu

Shin

et al. 2017

Stem Cell Reports

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SummaryBone marrow-derived mesenchymal stem cells (BMSCs) are proposed as the cells of origin of several subtypes of osteosarcoma (OS). However, signals that direct BMSCs to form different subtypes of OS are unclear. Here we show that the default tumor type from spontaneously transformed p53 knockout (p53_KO) BMSCs is osteoblastic OS. The development of this default tumor type caused by p53 loss can be overridden by various oncogenic signals: RAS reprograms p53_KO BMSCs into undifferentiated sarcoma, AKT enhances osteoblastic OS, while cFOS promotes chondroblastic OS formation. We focus on studying the mechanism of cFOS-induced chondroblastic OS formation. Integrated genome-wide studies reveal a regulatory mechanism whereby cFOS binds to the promoter of a key chondroblastic transcription factor, Sox9, and induces its transcription in BMSCs. Importantly, SOX9 mediates cFOS-induced cartilage formation in chondroblastic OS. In summary, oncogenes determine tumor types derived from BMSCs, and the cFOS-SOX9 axis is critical for chondroblastic OS formation.

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A RUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells

Cited by 37 publications

References 39 publications

Biology and pathogenesis of human osteosarcoma (Review)

Biology and pathogenesis of human osteosarcoma (Review)

The interaction between RUNX2 and core binding factor beta as a potential therapeutic target in canine osteosarcoma

cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma

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