The prognosis of glioblastoma (GBM) is usually poor even following treatment with the first-line chemotherapeutic agent temozolomide (TMZ). One most known resistant mechanism is the presence of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). However, compared with MGMT-mediated innate TMZ resistance, the development of acquired resistance is considered more complex with multi-factorial involvement such as the presence of cancer stem cells (CSCs). In this study, we treated the MGMT-negative GBM cells with TMZ to investigate the acquired resistance, and found that both histone deacetylases (HDACs) and Sp1 are key factors protecting GBM against TMZ. These results include the following: (1) Stemness markers were highly increased in TMZ-resistant GBMs; (2) The activity of HDACs affected the stem-like characteristics and cell survival of GBM stem cells (GSCs); (3) An HDAC1/2/6-selective inhibitor MPT0B291 increased TMZ-sensitivity and induced senescence in TMZ-resistant cells; (4) MPT0B291 suppressed anti-senescence genes (hTERT and BMI1) expression via inhibition Sp1 transactivation; (5) Both HDACs and Sp1 were elevated and interacted with each other in GSCs and resistant GBM cells; (6) TMZ treatment induced Sp1 deacetylation, but MPT0B291 attenuated that. In summary, we verified that HDACs increases Sp1 activation via protein deacetylation and causes Sp1-downstream target upregulation, which may enrich stemness properties and protect GBM against chemotherapeutic drugs.
Date:
2018-07
Relation:
Cancer Research. 2018 Jul;78(13, Suppl.):Meeting Abstract 5905.
