Wen-Bin Yang1,2, Che-Chia Hsu1,3, Tsung-I Hsu2,4, Jing-Ping Liou2,5, Kwang-Yu Chang6, Pin-Yuan Chen7, Jr-Jiun Liu2, Shung-Tai Yang8, Jia-Yi Wang9, Shiu-Hwa Yeh10, Ruei-Ming Chen1,4, Wen-Chang Chang1, Jian-Ying Chuang2,4,11. 1. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. 2. The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. 3. Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, North Carolina, USA. 4. TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. 5. School of Pharmacy, Taipei Medical University, Taipei, Taiwan. 6. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. 7. Department of Neurosurgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. 8. Division of Neurosurgery, Taipei Medical University-Shuang Ho Hospital Ministry of Health and Welfare, New Taipei, Taiwan. 9. Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan. 10. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan. 11. Cell Physiology and Molecular Image Research Center, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
Abstract
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.
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.
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