MMP14 Contributes to HDAC Inhibition-Induced Radiosensitization of Glioblastoma

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment method of GBM. However, the intrinsic radioresistance of GBM cells is a key reason of poor therapeutic efficiency. Recently, many studies have shown that using the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy may improve the prognosis of GBM patients, but the underlying molecular mechanisms remain unclear. In this study, Gene Expression Omnibus (GEO) datasets GSE153982 and GSE131956 were analyzed to evaluate radiation-induced changes of gene expression in GBM without or with SAHA treatment, respectively. Additionally, the survival-associated genes of GBM patients were screened using the Chinese Glioma Genome Atlas (CGGA) database. Taking the intersection of these three datasets, 11 survival-associated genes were discovered to be activated by irradiation and regulated by SAHA. The expressions of these genes were further verified in human GBM cell lines U251, T98G, and U251 homologous radioresistant cells (U251R) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was found that MMP14 mRNA was considerably highly expressed in the radioresistant cell lines and was reduced by SAHA treatment. Transfection of MMP14 siRNA (siMMP14) suppressed cell survivals of these GBM cells after irradiation. Taken together, our results reveal for the first time that the MMP14 gene contributed to SAHA-induced radiosensitization of GBM.

Construction of a prognostic classifier and prediction of the immune landscape and immunosuppressive molecules in gliomas based on combination of inflammatory response-related genes and angiogenesis-associated genes

“…52 Past studies have shown that the use of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy improves the prognosis of GBM patients, and Zhou Y et al first revealed the role of the MMP14 gene on SAHA-induced radiosensitization in GBM. 53 N-myc interactor (NMI) is a member of the Myc family of oncogenes, which presents an intimate relevance to the onset and progression of tumors. 54 The NMI polymorphism was previously shown to be strongly associated with genetic susceptibility to gliomas in the Chinese Han population.…”

Shedding light on function of long non-coding RNAs (lncRNAs) in glioblastoma

“…Noteworthy, AMPK overexpression leads to upregulation of ATM via Sp1 to increase radio-resistance property of GBM cells [ 148 ]. Therefore, appropriate response of GBM cells to radiotherapy is a troublesome problem [ 149 , 150 ]. Most of the studies have focused on the role of lncRNAs in mediating chemo-resistance in GBM.…”