Inhibition of DNA methyltransferases, histone deacetylases and lysine-specific demethylase-1 suppresses the tumorigenicity of the ovarian cancer ascites cell line SKOV3

Meng, Fanliang; Sun, Guizhi; Zhong, Ming; Yu, Yang; Brewer, Molly

doi:10.3892/ijo.2013.1960

Cited by 32 publications

(17 citation statements)

References 30 publications

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“…Recent reports indicate tumorigenicity and metastasis of ovarian cancer cells is significantly suppressed by the combination of HDAC inhibitor TSA and 5-Aza-dC in xenograft mouse models [78]. Thus, we determined the effects of a combination of TSA and 5-Aza-dC treatments on RGS10 expression and cell viability in chemoresistant ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 96%

Inhibition of HDAC1 and DNMT1 Modulate RGS10 Expression and Decrease Ovarian Cancer Chemoresistance

et al. 2014

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RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance.

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Section: Discussionmentioning

confidence: 96%

Inhibition of HDAC1 and DNMT1 Modulate RGS10 Expression and Decrease Ovarian Cancer Chemoresistance

et al. 2014

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“…5-azacytidine and its deoxy derivative 5-aza-2′ deoxycytidine are two FDA approved drugs used in the treatment of AML [43]. Along with the role of these drugs blocking cell proliferation in vitro and in vivo , several studies have suggested a potential role for these drugs in suppressing the metastatic phenotype [44; 45; 46; 47]. For example, Aza has been reported to inhibit invasiveness of human breast, ovarian and non-small lung cancer cell lines [48; 49].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182

et al. 2015

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Accumulating evidence indicates that microRNAs (miRs) regulate cancer metastasis. We have shown that miR-182 drives sarcoma metastasis in vivo by coordinated regulation of multiple genes. Recently, we also demonstrated that in a subset of primary sarcomas that metastasize to the lung, miR-182 expression is elevated through binding of MyoD1 to the miR-182 promoter. However, it is not known if there are also transcription factors that inhibit miR-182 expression. Defining negative regulators of miR-182 expression may help explain why some sarcomas do not metastasize and may also identify pathways that can modulate miR-182 for therapeutic benefit. Here, we use an in silico screen, chromatin-immunoprecipitation, and luciferase reporter assays to discover that Kruppel like factor -3 (Klf-3) is a novel transcriptional repressor of miR-182. Knockdown of Klf-3 increases miR-182 expression, and stable overexpression of Klf-3, but not a DNA-binding mutant Klf-3, decreases miR-182 levels. Klf-3 expression is downregulated in both primary mouse and human metastatic sarcomas, and Klf-3 levels negatively correlate with miR-182 expression. Interestingly, Klf-3 also negatively regulates MyoD1, suggesting an alternative mechanism for Klf-3 to repress miR-182 expression in addition to direct binding of the miR-182 promoter. Using Methylation Specific PCR (MSP) and pyrosequencing assays, we found that Klf-3 is epigenetically silenced by DNA hypermethylation both in mouse and human sarcoma cells. Finally, we show the DNA methylation inhibitor 5′Azacytidine (Aza) restores Klf-3 expression, while reducing miR-182 levels. Thus, our findings suggest that demethylating agents could potentially be used to modulate miR-182 levels as a therapeutic strategy.

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“…Hence, LSD1 inhibition by HCI-2509 might be applied in combined therapeutical strategies of tumor treatment. Indeed, LSD1 inhibition was recently combined with HDAC and EZH2 inhibitors in treatment strategies in acute myeloid leukemia and glioblastoma, as well as in breast and ovarian cancer (Duan et al, 2017;Huang et al, 2012;Meng et al, 2013;Singh et al, 2011;Wen et al, 2018). However, the treatment approaches in which LSD1 inhibition by HCI-2509 could be combined with chemotherapeutical agents that induce apoptosis and tumor recession indicate innovative promising concepts.…”

Section: Discussionmentioning

confidence: 99%

Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

et al. 2018

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Lung adenocarcinoma (LUAD) is the most prevalent subtype of non‐small cell lung cancer. Despite the development of novel targeted and immune therapies, the 5‐year survival rate is still only 21%, indicating the need for more efficient treatment regimens. Lysine‐specific demethylase 1 (LSD1) is an epigenetic eraser that modifies histone 3 methylation status, and is highly overexpressed in LUAD. Using representative human cell culture systems and two autochthonous transgenic mouse models, we investigated inhibition of LSD1 as a novel therapeutic option for treating LUAD. The reversible LSD1 inhibitor HCI‐2509 significantly reduced cell growth with an IC 50 of 0.3–5 μm in vitro, which was linked to an enhancement of histone 3 lysine methylation. Most importantly, growth arrest, as well as inhibition of the invasion capacities, was independent of the underlying driver mutations. Subsequent expression profiling revealed that the cell cycle and replication machinery were prominently affected after LSD1 inhibition. In addition, our data provide evidence that LSD1 blockade significantly interferes with EGFR downstream signaling. Finally, our in vitro results were confirmed by preclinical therapeutic approaches, including the use of two autochthonous transgenic LUAD mouse models driven by either EGFR or KRAS mutations. Importantly, LSD1 inhibition resulted in significantly lower tumor formation and a strong reduction in tumor progression, which were independent of the underlying mutational background of the mouse models. Hence, our findings provide substantial evidence indicating that tumor growth of LUAD can be markedly decreased by HCI‐2509 treatment, suggesting its use as a single agent maintenance therapy or combined therapeutical application in novel concerted drug approaches.

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Inhibition of DNA methyltransferases, histone deacetylases and lysine-specific demethylase-1 suppresses the tumorigenicity of the ovarian cancer ascites cell line SKOV3

Cited by 32 publications

References 30 publications

Inhibition of HDAC1 and DNMT1 Modulate RGS10 Expression and Decrease Ovarian Cancer Chemoresistance

Inhibition of HDAC1 and DNMT1 Modulate RGS10 Expression and Decrease Ovarian Cancer Chemoresistance

Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182

Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

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