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.