HMGA2 sustains self-renewal and invasiveness of glioma-initiating cells

Zhong, Xiaoling; Luo, Xin; Li, Yamu; Cheng, Man; Wang, Wen; Tian, Kuan; Mu, Lili; Zeng, Tao; Liu, Ying; Jiang, Xiaobing; Yu, Luyang; Gao, Liang; Zhou, Yan

doi:10.18632/oncotarget.9744

Cited by 23 publications

(23 citation statements)

References 56 publications

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“…Several reporter systems to study endogenous promoter activation by HMGA2 have previously been reported (22,23). We fortuitously discovered that in HeLa cells, which do not express detectable levels of endogenous HMGA2, C-terminally FLAG-tagged human HMGA2 significantly enhanced Renilla luciferase expression from a reporter gene driven by the herpes simplex virus thymidine kinase (HSV-TK) promoter.…”

Section: Resultsmentioning

confidence: 99%

Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Peter¹,

Yu²,

Ivanyi‐Nagy³

et al. 2016

Nucleic Acids Res

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HMGA2 is an important chromatin factor that interacts with DNA via three AT-hook domains, thereby regulating chromatin architecture and transcription during embryonic and fetal development. The protein is absent from differentiated somatic cells, but aberrantly re-expressed in most aggressive human neoplasias where it is causally linked to cell transformation and metastasis. DNA-binding also enables HMGA2 to protect cancer cells from DNA-damaging agents. HMGA2 therefore is considered to be a prime drug target for many aggressive malignancies. Here, we have developed a broadly applicable cell-based reporter system which can identify HMGA2 antagonists targeting functionally important protein domains, as validated with the known AT-hook competitor netropsin. In addition, high-throughput screening can uncover functional links between HMGA2 and cellular factors important for cell transformation. This is demonstrated with the discovery that HMGA2 potentiates the clinically important topoisomerase I inhibitor irinotecan/SN-38 in trapping the enzyme in covalent DNA-complexes, thereby attenuating transcription.

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Section: Resultsmentioning

confidence: 99%

Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Peter¹,

Yu²,

Ivanyi‐Nagy³

et al. 2016

Nucleic Acids Res

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“…Moreover, TF HMGA2 was found to be expressed in both GSCs and pericytes of GBM. Depletion of HMGA2 in GSCs abrogates their potential for pericyte differentiation, indicating its role in self-renewal properties of GSCs (Zhong et al, 2016). …”

Section: The Microenvironment Of Gscs: the Tumor Vascular Nichementioning

confidence: 99%

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

et al. 2016

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Glioblastoma multiforme (GBM), grade IV astrocytoma, is the most fatal malignant primary brain tumor. GBM contains functional subsets of cells called glioblastoma stem-like cells (GSCs), which are radioresistant and chemoresistant and eventually lead to tumor recurrence. Recent studies showed that GSCs reside in particular tumor niches that are necessary to support their behavior. To successfully eradicate GBM growth and recurrence, new strategies selectively targeting GSCs and/or their microenvironmental niche should be designed. In this regard, here we focus on elucidating the molecular mechanisms that govern these GSC properties and on understanding the mechanism of the microenvironmental signals within the tumor mass. Moreover, to overcome the blood–brain barrier, which represents a critical limitation of GBM treatments, a new drug delivery system should be developed. Nanoparticles can be easily modified by different methods to facilitate delivery efficiency of chemotherapeutics, to enhance the accumulation within the tumors, and to promote the capacity for targeting the GSCs. Therefore, nanotechnology has become the most promising approach to GSC-targeting therapy. Additionally, we discussed the future of nanotechnology-based targeted therapy and point out the disadvantages that should be overcome.

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“…C). It was previously shown that Lin28 located upstream of HMGA2 can upregulate HMGA2 (Mao et al ., ) and that HMGA2 promotes GB stem cell renewal and tumor initiation in GB cells (Zhong et al ., ). In concordance with the Dov‐mediated reduction in cellular Lin28 and HMGA2 levels, we showed that Dov reduced the number of GB spheres in a concentration‐dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Our data in GB cells showed that Dov downregulates the stem cell factor and RNA‐binding protein Lin28A and its target HMGA2, identifying a hitherto unknown role of Dov as an inhibitor of the LIN28/Let‐7/HMGA2 axis in human GB. In agreement with the well‐known function of HMGA2 in promoting self‐renewal of stem cells (Zhong et al ., ) and GB tumor initiation capability (Kaur et al ., ), Dov attenuated GB sphere formation and increased apoptosis in sphere‐forming GB cells. HMGA2 expression is controlled by specific Let‐7 microRNA members that bind to the 3′UTR of HMGA2 to cause reduced mRNA stability and translation (Hammond and Sharpless, ).…”

Section: Discussionmentioning

confidence: 99%

Dovitinib enhances temozolomide efficacy in glioblastoma cells

et al. 2017

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The multikinase inhibitor and FDA-approved drug dovitinib (Dov) crosses the blood–brain barrier and was recently used as single drug application in clinical trials for GB patients with recurrent disease. The Dov-mediated molecular mechanisms in GB cells are unknown. We used GB patient cells and cell lines to show that Dov downregulated the stem cell protein Lin28 and its target high-mobility group protein A2 (HMGA2). The Dov-induced reduction in pSTAT3Tyr705 phosphorylation demonstrated that Dov negatively affects the STAT3/LIN28/Let-7/HMGA2 regulatory axis in GB cells. Consistent with the known function of LIN28 and HMGA2 in GB self-renewal, Dov reduced GB tumor sphere formation. Dov treatment also caused the downregulation of key base excision repair factors and O6-methylguanine-DNA-methyltransferase (MGMT), which are known to have important roles in the repair of temozolomide (TMZ)-induced alkylating DNA damage. Combined Dov/TMZ treatment enhanced TMZ-induced DNA damage as quantified by nuclear γH2AX foci and comet assays, and increased GB cell apoptosis. Pretreatment of GB cells with Dov (‘Dov priming’) prior to TMZ treatment reduced GB cell viability independent of p53 status. Sequential treatment involving ‘Dov priming’ and alternating treatment cycles with TMZ and Dov substantially reduced long-term GB cell survival in MGMT+ patient GB cells. Our results may have immediate clinical implications to improve TMZ response in patients with LIN28+/ HMGA2+ GB, independent of their MGMT methylation status.

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HMGA2 sustains self-renewal and invasiveness of glioma-initiating cells

Cited by 23 publications

References 56 publications

Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

Dovitinib enhances temozolomide efficacy in glioblastoma cells

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