國家衛生研究院 NHRI:Item 3990099045/12654
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    題名: Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma
    作者: Yang, WB;Hsu, CC;Hsu, TI;Liou, JP;Chang, KY;Chen, PY;Liu, JJ;Yang, ST;Wang, JY;Yeh, SH;Chen, RM;Chang, WC;Chuang, JY
    貢獻者: National Institute of Cancer Research;Institute of Biotechnology and Pharmaceutical Research
    摘要: BACKGROUND: Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemo-resistance and glioblastoma recurrence. The Sp1 transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known. METHODS: Sp1 acetylation in temozolomide-resistant cells and stem-like tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the HDAC/Sp1 axis on malignant growth were examined using cell proliferation-related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with ChIP-seq and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis. RESULTS: We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating BMI1 and hTERT, as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolylsulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stem-like tumorspheres. CONCLUSIONS: Our study uncovers a previously unknown regulatory mechanism in which the HDAC6-Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance.
    日期: 2020-10
    關聯: Neuro-Oncology. 2020 Oct;22(10):1439-1451.
    Link to: http://dx.doi.org/10.1093/neuonc/noaa103
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1522-8517&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000593120000008
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85092943923
    顯示於類別:[張光裕] 期刊論文
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