Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

McGuire, Jeremy; Nerlakanti, Niveditha; Lo, Chen Hao; Tauro, Marilena; Utset-Ward, Thomas J; Reed, Damon R.; Lynch, Conor C.

doi:10.1002/ijc.33046

Cited by 20 publications

(24 citation statements)

References 27 publications

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“…OS metastasis and chemoresistance are the key clinical factors leading to a low five-year survival rate of approximately 30% in patients with remote involvement [3][4][5][6]. Recent studies have shown that tumor suppressor and/or oncogene mutations, copy number alterations, fusion genes, and epigenetic dysregulation may lead to tumor formation, cancer metastasis, and multidrug resistance [7][8][9][10][11]. These distinct characteristics may pose as vulnerabilities that can be exploited as treatment targets.…”

Section: Introductionmentioning

confidence: 99%

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

Torres

VanCleave

Vollmer

et al. 2021

Cancers

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Dysregulation of histone deacetylases (HDACs) is associated with the pathogenesis of human osteosarcoma, which may present an epigenetic vulnerability as well as a therapeutic target. Domatinostat (4SC-202) is a next-generation class I HDAC inhibitor that is currently being used in clinical research for certain cancers, but its impact on human osteosarcoma has yet to be explored. In this study, we report that 4SC-202 inhibits osteosarcoma cell growth in vitro and in vivo. By analyzing cell function in vitro, we show that the anti-tumor effect of 4SC-202 involves the combined induction of cell-cycle arrest at the G2/M phase and apoptotic program, as well as a reduction in cell invasion and migration capabilities. We also found that 4SC-202 has little capacity to promote osteogenic differentiation. Remarkably, 4SC-202 revised the global transcriptome and induced distinct signatures of gene expression in vitro. Moreover, 4SC-202 decreased tumor growth of established human tumor xenografts in immunodeficient mice in vivo. We further reveal key targets regulated by 4SC-202 that contribute to tumor cell growth and survival, and canonical signaling pathways associated with progression and metastasis of osteosarcoma. Our study suggests that 4SC-202 may be exploited as a valuable drug to promote more effective treatment of patients with osteosarcoma and provide molecular insights into the mechanism of action of class I HDAC inhibitors.

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Section: Introductionmentioning

confidence: 99%

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

Torres

VanCleave

Vollmer

et al. 2021

Cancers

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“…Romidepsin, which is a histone deacetylase (HDAC) inhibitor, is approved for the treatment of hematologic malignancies and shows limited activity in a number of solid tumor types with notable toxicities [50][51][52][53][54] . Several groups have reported that HDAC inhibitors prevent the growth of OS cell lines in vitro and in vivo 55,56) . Although the effects of romidepsin on ESOS have never been reported, our data support the hypothesis that romidepsin may represent a potential strategy for OS and ESOS.…”

Section: Discussionmentioning

confidence: 99%

Proteogenomic approach to drug targets in osteosarcomas with different original sites

et al. 2021

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Regulation of kinase activity plays a crucial role in carcinogenesis and cancer progression. Mutations in the activity domain of kinases are extensively investigated as therapeutic targets. We examined anti-proliferative anti-cancer drugs and drug targets via the multi-omics approach: (i) comprehensive kinase activity assay, (ii) high-throughput drug screening, and (iii) genomic sequencing. Two osteosarcomas cell lines, NCC-OS1-C1 and NCC-ESOS1-C1 derived from bone and soft tissue respectively, were used. Genetic alterations were examined by NCC Oncopanel based on the next-generation sequencing technology and SNP array. One hundred kinases were monitored by the PamStation 12, an in vitro kinase assay. The anti-proliferative effects of 214 FDA-approved anti-cancer drugs were examined. Mutation of PIK3CA and deletion of CDKN2A were identified in NCC-ESOS1-C1 and druggable genetic alterations were not identified in the NCC-OS1-C1. PI3K-AKT pathway or CDKN2A inhibitors did not show significant effects on these cell lines. Comprehensive kinomic assay revealed no remarkable differences on these osteosarcoma cells (R 2 =0.99). The two cells shared similar kinase activity profiles for FES, FER, PDGFR-β, VEGFR2, and Wee1. Anti-proliferative effects of anti-cancer drugs on NCC-OS1-C1 and NCC-ESOS1 cells showed remarkable differences. Significant responses to romidepsin and trabectedin were observed for both. Eribulin was effective on NCC-OS1-C1; ifosfamide and dacarbazine were effective on NCC-ESOS1-C1 only. Hence, investigating kinase activities and genetic alterations will lead to predict the effects of kinase inhibitors. The different status of kinase mutations, activities, and response to inhibitors should be integrated. Multi-omics experiments and data integration are crucial in understanding cancer progression and developing novel therapies.

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“…In addition, HDAC1 was significantly downregulated in our transcriptome analysis. Treatment with panobinostat, a broad spectrum HDAC inhibitor, showed decreased OS growth and lung metastasis in an orthotopic xenograft model using human OS cell lines (29). In this report, treatment with the selective inhibitor for HDAC1/2 compromised the growth of OS in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

miRNA-34c suppresses osteosarcoma progression in vivo by targeting Notch and E2F

Bae¹,

Zeng²,

Chen

et al. 2021

Preprint

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The expression of microRNAs (miRNAs) is dysregulated in many types of cancers including osteosarcoma (OS) due to genetic and epigenetic alterations. Among these, miR-34c, an effector of tumor suppressor P53 and an upstream negative regulator of Notch signaling in osteoblast differentiation, is dysregulated in OS. Here, we demonstrated a tumor suppressive role of miR-34c in OS progression using in vitro assays and in vivo genetic mouse models. We found that miR-34c inhibits the proliferation and the invasion of metastatic OS cells, which resulted in reduction of the tumor burden and increased overall survival in an orthotopic xenograft model. Moreover, the osteoblast specific over expression of miR-34c increased survival in the osteoblast specific p53 mutant OS mouse model. We found that miR-34c regulates the transcription of several genes in Notch signaling (NOTCH1, JAG1 and HEY2) and in p53 mediated cell cycle and apoptosis (CCNE2, E2F5, E2F2 and HDAC1). More interestingly, we found that the metastatic free survival probability was increased among a patient cohort from TARGET OS which has lower expression of direct targets of miR-34c that was identified in our transcriptome analysis such as E2F5 and NOTCH1. In conclusion, we demonstrate that miR-34c is a tumor suppressive miRNA in OS progression in vivo. In addition, we highlight the therapeutic potential of targeting miR-34c in OS.

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Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

Cited by 20 publications

References 27 publications

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

Proteogenomic approach to drug targets in osteosarcomas with different original sites

miRNA-34c suppresses osteosarcoma progression in vivo by targeting Notch and E2F

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