Decitabine represses osteoclastogenesis through inhibition of RANK and NF-κB

Guan, Hanfeng; Mi, Bobin; Li, Yong; Wu, Wei; Tan, Peng; Fang, Zhong; Li, Jing; Zhang, Yong; Li, Feng

doi:10.1016/j.cellsig.2015.02.006

Cited by 18 publications

(15 citation statements)

References 24 publications

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“…Few data concerning epigenetic regulation of transcription factors are available. Some studies have reported that 5azadC induces a decrease in AP-1 expression in bone marrow mononuclear cells [ 36 ], an increase in CEBPα but a decrease in CEBPγ expression in acute myeloid leukemia cells [ 37 ] and an increase in CEBPα expression in three HPV-negative head and neck squamous cell carcinoma cell lines [ 38 ]. In Ca Ski and SiHa cells, none of the studied transcription factors (either activator or repressor) appeared significantly increased or decreased by 5azadC treatment.…”

Section: Discussionmentioning

confidence: 99%

5azadC treatment upregulates miR-375 level and represses HPV16 E6 expression

et al. 2017

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High-risk human papillomaviruses are the etiological agents of cervical cancer and HPV16 is the most oncogenic genotype. Immortalization and transformation of infected cells requires the overexpression of the two viral oncoproteins E6 and E7 following HPV DNA integration into the host cell genome. Integration often leads to the loss of the E2 open reading frame and the corresponding protein can no longer act as a transcriptional repressor on p97 promoter. Recently, it has been proposed that long control region methylation also contributes to the regulation of E6/E7 expression.To determine which epigenetic mechanism is involved in HPV16 early gene regulation, 5-aza-2′-deoxycytidine was used to demethylate Ca Ski and SiHa cell DNA. Decreased expression of E6 mRNA and protein levels was observed in both cell lines in an E2-independent manner. E6 repression was accompanied by neither a modification of the main cellular transcription factor expression involved in long control region regulation, nor by a modification of the E6 mRNA splicing pattern. In contrast, a pronounced upregulation of miR-375, known to destabilize HPV16 early viral mRNA, was observed. Finally, the use of miR-375 inhibitor definitively proved the involvement of miR-375 in E6 repression. These results highlight that cellular DNA methylation modulates HPV16 early gene expression and support a role for epigenetic events in high-risk HPV associated-carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

5azadC treatment upregulates miR-375 level and represses HPV16 E6 expression

et al. 2017

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“…The effect of 5-Aza-dC on NF-κB activity is cell-type dependent. 5-Aza-dC activated NF-κB signaling in Burkitt lymphoma (28) and in AML (49), but inhibited NF-κB activity in osteoclasts (44). Of note, although in our experiments we observed significant upregulation of NF-κB and STAT target genes, this was not mediated by increased nuclear translocation of these transcription factors.…”

Section: Discussionmentioning

confidence: 44%

“…In the human AML cell line NB4 and in freshly isolated AML cells, 5-Aza-dC also stimulated ERK phosphorylation (43). In other normal and malignant cell types including osteoclasts (44), acute lymphoblastic leukemia (45), and lung cancer cell lines (46) 5-Aza-dC attenuated MEK/ ERK activity, inter alia by reactivating epigenetically silenced negative regulators. JAK-STAT signaling is inhibited by 5-Aza-dC, in particular by the reactivation of JAK-STAT inhibitors (47,48).…”

Section: Discussionmentioning

confidence: 99%

Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: A rationale for combination with small molecular weight inhibitors

Swerev

Wirth

Ushmorov

2016

International Journal of Oncology

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DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities. Although efficacy of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side‑effect of the demethylating agent 5‑azacytidine in a patient with myelodysplastic syndrome. We investigated molecular mechanisms of decitabine (5‑Aza‑dC) antitumor activity in cHL using gene expression profiling followed by gene set enrichment analysis. We found that 5‑Aza‑dC inhibits growth of cHL cell lines at clinically relevant concentrations of 0.25‑2 µM. The antitumor effect of 5‑Aza‑dC was associated with induction of genes, which negatively regulate cell cycle progression (e.g. CDKN1A and GADD45A). Surprisingly, we also observed significant enrichment of pro‑survival pathways like MEK/ERK, JAK‑STAT and NF‑κB, as well as signatures comprising transcription‑activating genes. Among the upregulated pro‑survival genes were the anti‑apoptotic genes BCL2 and BCL2L1, as well as genes involved in transduction of growth and survival signals like STAT1, TLR7, CD40 and IL-6. We therefore analyzed whether interference with these pro‑survival pathways and genes would potentiate the antitumor effect of 5‑Aza‑dC. We could show that the BCL2/BCL2L1 inhibitor ABT263, the JAK‑STAT inhibitors fedratinib and SH‑4‑54, the AKT inhibitor KP372‑1, the NF‑κB inhibitor QNZ, as well as the bromodomain and extraterminal (BET) family proteins inhibitor JQ1 acted synergistically with 5‑Aza‑dC. We conclude that targeting of oncogenic pathways of cHL may improve efficacy of DNA-demethylating therapy in cHL.

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“…M-CSF upregulates RANK expression on osteoclast precursors and promotes osteoclast differentiation, whereas RANKL binds to RANK and cause the activation of nuclear transcriptional regulators (11). The recruitment of variable adaptor molecules then activates downstream signaling pathways, includes the NF-kB and PI3K/AKT pathways, thereby initiating osteoclast formation and activity (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Serum- and Glucocorticoid-inducible Kinase 1 is Essential for Osteoclastogenesis and Promotes Breast Cancer Bone Metastasis

Zheng

Song

et al. 2020

Molecular Cancer Therapeutics

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◥Bone metastasis is a severe complication associated with various carcinomas. It causes debilitating pain and pathologic fractures and dramatically impairs patients' quality of life. Drugs aimed at osteoclast formation significantly reduce the incidence of skeletal complications and are currently the standard treatment for patients with bone metastases. Here, we reported that serum-and glucocorticoid-inducible kinase 1 (SGK1) plays a pivotal role in the formation and function of osteoclasts by regulating the Ca 2þ release-activated Ca 2þ channel Orai1. We showed that SGK1 inhibition represses osteoclastogenesis in vitro and prevents bone loss in vivo. Furthermore, we validated the effect of SGK1 on bone metastasis by using an intracardiac injection model in mice. Inhibition of SGK1 resulted in a significant reduction in bone metastasis. Subsequently, the Oncomine and the OncoLnc database were employed to verify the differential expression and the association with clinical outcome of SGK1 gene in patients with breast cancer. Our data mechanistically demonstrated the regulation of the SGK1 in the process of osteoclastogenesis and revealed SGK1 as a valuable target for curing bone metastasis diseases. Materials and Methods ReagentsGSK650394 and BTP2 was purchased from Sigma-Aldrich. Soluble recombinant human M-CSF and mouse RANKL were obtained from PeproTech.

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Decitabine represses osteoclastogenesis through inhibition of RANK and NF-κB

Cited by 18 publications

References 24 publications

5azadC treatment upregulates miR-375 level and represses HPV16 E6 expression

5azadC treatment upregulates miR-375 level and represses HPV16 E6 expression

Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: A rationale for combination with small molecular weight inhibitors

Serum- and Glucocorticoid-inducible Kinase 1 is Essential for Osteoclastogenesis and Promotes Breast Cancer Bone Metastasis

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