Histone deacetylase 2 is involved in <scp>DNA</scp> damage‐mediated cell death of human osteosarcoma cells through stimulation of the <scp>ATM</scp>/p53 pathway

Sun, Dan; Yu, Meng; Li, Yuanyuan; Xing, Haotian; Gao, Ying; Huang, Zhihong; Hao, Wenjun; Lu, Kaining; Kong, Chuize; Shimozato, Osamu; Ozaki, Toshinori; Zhu, Yuyan

doi:10.1002/2211-5463.12585

Cited by 14 publications

(10 citation statements)

References 25 publications

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“…Interestingly, it was proposed that CSCs chemo-resistance is associated with their enhanced DNA damage response ( Abad et al, 2020 ). HDACs participate in the DNA damage response particularly in the early event ( Sun et al, 2019 ) and even more interestingly CDDP treatment induced HDACs in tumor cells, thus contributing to resistance and to the expansion of CSCs subpopulation ( Wang et al, 2017 ). Indeed, HDACi treatment impairs DNA repair mechanisms thus potentiating CDDP antitumor effect ( Gomez-Gonzalez et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

Iannelli

Zotti

Roca

et al. 2020

Front. Cell Dev. Biol.

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Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute.

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Section: Discussionmentioning

confidence: 99%

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

Iannelli

Zotti

Roca

et al. 2020

Front. Cell Dev. Biol.

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“…In addition, it may be hypothesized that HDAC2 could acquire the tumor-suppressive function observed in osteosarcoma. Recently, it has been demonstrated that HDAC2 binds to tumor suppressor p53 and augments its transcriptional activity in p53-wild-type osteosarcoma cells following DNA damage, indicating that the tumor-suppressive activity of HDAC2 may be dependent, at least in part, on p53 (41). Whether the functional conversion of HDAC2 could be dependent on p53, and whether p53 could directly regulate the expression of miR-489-3p, will be further investigated.…”

Section: Discussionmentioning

confidence: 99%

miR‑489‑3p inhibits proliferation and migration of bladder cancer cells through downregulation of histone deacetylase 2

Sun

Xin

et al. 2020

Oncol Lett

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Since human bladder cancer (BC) is a common malignancy of the urinary system with poor prognosis, it is crucial to clarify the molecular mechanisms of BC development and progression. To the best of our knowledge, the current study demonstrated for the first time that miR-489-3p suppressed BC cell-derived tumor growth in vivo via the downregulation of histone deacetylase 2 (HDAC2). According to the results, expression levels of miR-489-3p were lower in BC tissues compared with corresponding normal tissues. Expression of miR-489-3p mimics in BC-derived T24 and 5637 cells resulted in a significant reduction in proliferation and migration rates. Furthermore, bioinformatics analyses indicated that HDAC2 may be a potential downstream target of miR-489-3p. In contrast to miR-489-3p, HDAC2 was expressed at higher levels in BC tissues compared with corresponding normal tissues. Additionally, small interfering RNA-mediated knockdown of HDAC2 caused a marked decrease in the proliferation and migration rates of T24 and 5637 cells. Consistent with these observations, expression of miR-489-3p mimics attenuated the growth of xenograft tumors arising from T24 cells and resulted in HDAC2 downregulation. In conclusion, the results of the current study indicated that the miR-489-3p/HDAC2 axis serves a role in the development and/or the progression of BC and may be a potential molecular target for the development of a novel strategy to treat patients with BC.

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“…25 Dan Sun et al demonstrated that p53-HDAC2 axis plays a vital role in the regulation of the DNA damage response and contributes to chemo-sensitivity of osteosarcoma cells. 26 Jing Li et al reported that HDAC2 could upregulate the expression of IL-6 and trigger the migration of osteosarcoma cells, implying that targeted inhibition of HDAC2/IL-6 might be a potential approach for osteosarcoma therapy. 27 In this study, by combination analysis of multiple gene expression data of osteosarcoma from GEO, TCGA and Kaplan-Meier Plotter cohorts, we demonstrated that HDAC2 was overexpressed in osteosarcoma tissues, and acted as an unfavorable marker for patients' survival.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase-2 Serves as an Independent Prognostic Indicator in Osteosarcoma

Wang

et al. 2020

Preprint

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Background Osteosarcoma is the most common primary malignant tumor of skeleton in adolescence. Histone deacetylase 2 (HDAC2), a member of class I histone deacetylase, is putatively involved in tumorigenesis of human malignancies. This study aimed to evaluate the expression pattern and prognostic value of HDAC2 in osteosarcoma.Methods Four datasets were obtained from the gene expression omnibus (GEO) database to explore the expression and prognostic value of HDAC2. Level 3 mRNA expression profiles and clinical data were obtained in The Cancer Genome Atlas (TCGA) for validation. Expression pattern of HDAC2 were illustrated in GSE16088, GSE36001 and GSE42352. The prognostic value of HDAC2 was evaluated and validated by Kaplan-Meier analyses, receiver operating characteristic (ROC), concordance index (C-index) and calibration curve in GSE21257 and TCGA. Multivariate Cox regression analysis, nomogram, and decision curve analysis (DCA) were performed to assess the prognosis predictive capability. Protein-protein interaction (PPI) and gene set enrichment analysis (GSEA) were applied to further understand the molecular network and regulatory mechanisms.Results HDAC2 expression was significantly increased in osteosarcoma tissues. High HDAC2 expression was associated with tumor metastasis and chemotherapy efficacy. Kaplan-Meier analysis demonstrated that high HDAC2 predicted worse overall survival. The ROC curve showed good performance in survival prediction. Cox regression demonstrated that HDAC2 could be an independent prognostic indicator. GSEA revealed patients with high HDAC2 expression were enriched with multiple ontological signatures.Conclusions Elevated expression of HDAC2 may identify an aggressive subgroup in osteosarcoma and serve as an independent prognostic indicator in these patients.

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Histone deacetylase 2 is involved in DNA damage‐mediated cell death of human osteosarcoma cells through stimulation of the ATM/p53 pathway

Cited by 14 publications

References 25 publications

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

miR‑489‑3p inhibits proliferation and migration of bladder cancer cells through downregulation of histone deacetylase 2

Histone Deacetylase-2 Serves as an Independent Prognostic Indicator in Osteosarcoma

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