The existence of small numbers of stem-like cells, called glioma stem cells (GSCs), in human glioblastoma multiforme (GBM) is responsible for recurrence due to resistance to radiotherapy and chemotherapy. Inhibition of histone deacetylase 6 (HDAC6) enhanced radiosensitivity of cancer cells. However, the effect of inhibiting HDAC6 on sternness and radioresistance of GSCs and its molecular mechanism are largely unknown. In the present study, we found that HDAC6 was upregulated in GSC5 comparing to non-stem tumor cells. Inhibiting HDAC6 downregulated glioma-associated oncogene homolog 1 (Gli1), Patched (Ptch1 and Ptch2) receptors, components of SHH signal, expression and activity in GSC5. Restraining HDAC6 decreased cell proliferation, induces differentiation and increased apoptosis of GSC5 via inactivation of SHH/Gli1 signaling pathway. Moreover, HDAC6 inhibition decreased DNA damage repair capacity of GSCs through degradation of checkpoint kinase (CHIC) 1 caused by X-linked inhibitor of apoptosis (XIAP) downregulation, leading to elevated radiosensitivity. Taken together, these findings indicate that HDAC6 inhibition decreased sternness of GSCs and enhanced GSCs radiosensitivity through inactivating SHH/Gli1 pathway. This provides a promising novel drug target to overcome GSCs sternness and radioresistance. (C) 2017 Elsevier B.V. All rights reserved.
[1]Soochow Univ, Sch Radiol Med & Protect, Med Coll, Collaborat Innovat Ctr Radiat Med Jiangsu Higher, Suzhou 215123, Jiangsu, Peoples R China.
[2]Jilin Univ, Affiliated Hosp 1, Dept Neurosurg, Changchun 130021, Jilin, Peoples R China.
[3]Soochow Univ, Affiliated Hosp 1, Neurosurg & Brain & Nerve Res Lab, Suzhou 28006, Jiangsu, Peoples R China.
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