Increased activation of HDAC1/2/6 and Sp1 underlies therapeutic resistance and tumor growth in glioblastoma

Wen-Bin Yang, Che-Chia Hsu, Tsung-I Hsu, Jing-Ping Liou, Kwang-Yu Chang, Pin-Yuan Chen, Jr-Jiun Liu, Shung-Tai Yang, Jia-Yi Wang, Shiu-Hwa Yeh, Ruei-Ming Chen, Wen-Chang Chang, Jian-Ying Chuang

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1 引文 斯高帕斯(Scopus)

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 chemoresistance and glioblastoma recurrence. The specificity protein 1 (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 stemlike tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the histone deacetylase (HDAC)/Sp1 axis on malignant growth were examined using cell proliferation-related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with chromatin immunoprecipitation sequencing 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 B cell-specific Mo-MLV integration site 1 (BMI1) and human telomerase reverse transcriptase (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 azaindolyl sulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stemlike tumorspheres. CONCLUSION: 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.

原文英語
頁(從 - 到)1439-1451
頁數13
期刊Neuro-Oncology
22
發行號10
早期上線日期四月 24 2020
DOIs
出版狀態已發佈 - 十月 14 2020

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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