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Targeted suppression of ZNF217-induced AKT signaling inhibits tumor growth and metastasis in osteosarcoma

ABSTRACT: We previously identified ZNF217 as an oncogenic driver of a subset of osteosarcomas (OSAs) using the Sleeping Beauty (SB) transposon system. Here, we followed up investigating the role of ZNF217 in OSA and combined these studies with an orthotopic preclinical animal model and culture experiments. We found that targeting ZNF217-induced AKT signaling with a small molecule inhibitor is a promising approach to treating ZNF217+ OSAs. Here, we demonstrate that ZNF217 is involved in numerous facets of OSA transformation including proliferation, cell motility, colony formation, and ultimately promoting OSA growth, progression, and metastasis in part through AKT survival pathway modulation. Preclinical blockade of AKT signaling with nucleoside analogue triciribine (TCN) in ZNF217+ orthotopically-injected OSA cell lines reduced tumor growth, metastasis, and was well-tolerated. TCN treatment was also found to synergize with common broad-spectrum chemotherapeutic doxorubicin. Our data demonstrate that TCN treatment may be a relevant and efficacious therapeutic strategy for OSA patients with ZNF217+ and p-AKTSer473-rich tumors. With the recent revitalization of triciribine for clinical studies in other solid cancers (PTX-200, Prescient Therapeutics), our study provides rationale for further evaluation preclinically with the purpose of clinical evaluation in patients with incurable, ZNF217+ OSA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147413 | GEO | 2020/03/24

REPOSITORIES: GEO

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ZNF217 is an oncogene that promotes a basal phenotype and expansion of a progenitor cell population during breast cancer progression

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The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression

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2012-05-18 | GSE24727 | GEO

ZNF217 is an oncogene that promotes a basal phenotype and expansion of a progenitor cell population during breast cancer progression

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The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression

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Targeted suppression of ZNF217-induced AKT signaling inhibits tumor growth and metastasis in osteosarcoma

Project description:Targeted suppression of ZNF217-induced AKT signaling inhibits tumor growth and metastasis in osteosarcoma

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Identification of genes directly regulated by the oncogene ZNF217 using ChIP-chip assays

Project description:It has been proposed that ZNF217, which is amplified at 20q13 in various tumors, plays a key role during neoplastic transformation. ZNF217 has been purified in complexes that contain repressor proteins such as CtBP2, suggesting that it acts as a transcriptional repressor. However, the function of ZNF217 has not been well characterized due to a lack of known target genes. Using a global ChIP-chip approach, we have identified thousands of ZNF217 binding sites in three tumor cell lines (MCF7, SW480, and Ntera2). Further analysis of ZNF217 in Ntera2 cells has shown that many promoters are bound by ZNF217 and CtBP2, and that a subset of these promoters are activated upon removal of ZNF217. Thus, our in vivo studies corroborate the in vitro biochemical analyses of ZNF217-containing complexes and support the hypothesis that ZNF217 functions as transcriptional repressor. Gene ontology analysis shows that ZNF217 targets in Ntera2 cells are involved in organ development, suggesting that one function of ZNF217 may be to repress differentiation. Accordingly, we show that differentiation of Ntera2 cells with retinoic acid leads to downregulation of ZNF217. Our identification of thousands of ZNF217 target genes will enable further studies of the consequences of aberrant expression of ZNF217 during neoplastic transformation. Keywords: ChIP-chip

2007-01-25 | GSE6624 | GEO

Identification of genes directly regulated by the oncogene ZNF217 using ChIP-chip assays (Expression Data)

2007-01-25 | GSE6627 | GEO

Identification of genes directly regulated by the oncogene ZNF217 using ChIP-chip assays (Promoter Arrays)

2007-01-25 | GSE6625 | GEO

Identification of genes directly regulated by the oncogene ZNF217 using ChIP-chip assays (Promoter Arrays)

2010-06-12 | E-GEOD-6625 | biostudies-arrayexpress

Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with Eralpha

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2014-06-15 | GSE58326 | GEO

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