Abstract
BackgroundGliomas are the most common primary tumors in central nervous system. Despite advances in diagnosis and therapy, the prognosis of glioma remains gloomy. Autophagy is a cellular catabolic process that degrades proteins and damaged organelles, which is implicated in tumorigenesis and tumor progression. Autophagy related 4C cysteine peptidase (ATG4C) is an autophagy regulator responsible for cleaving of pro-LC3 and delipidation of LC3 II. This study was designed to investigate the role of ATG4C in glioma progression and temozolomide (TMZ) chemosensitivity.MethodsThe association between ATG4C mRNA expression and prognosis of gliomas patients was analyzed using the TCGA datasets. The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo. Ectopic xenograft nude mice model was established to investigate the effects of ATG4C on glioma growth in vivo.ResultsThe median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 × 10− 7). ATG4C mRNA expression was evidently increased with the rising of glioma grade (p = 2.97 × 10− 8). Knockdown ATG4C suppressed glioma cells proliferation by inducing cell cycle arrest at G1 phase. ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation. Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ. Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice.ConclusionATG4C is a potential prognostic predictor for glioma patient. Targeting ATG4C may provide promising therapy strategies for gliomas treatment.
Highlights
Gliomas are the most common primary tumors in central nervous system
Higher Autophagy related 4C cysteine peptidase (ATG4C) mRNA expression predicted poor prognosis for glioma patients In order to investigate the role of autophagy-related genes (ATGs) in prognosis of glioma patients, we developed an analysis flowchart (Additional file 1: Figure S1)
We observed that the mRNA expression of 13 ATGs (ATG3, ATG4A, ATG4C, ATG5, ATG7, ATG9B, ATG10, ATG12, ATG16L1, ATG2A, ATG2B, ATG9A and ATG16L2) were closely associated with the overall survival (OS) of glioma patients (Fig. 1a and Additional file 2: Figure S2)
Summary
Gliomas are the most common primary tumors in central nervous system. Temozolomide (TMZ) is considered to be the most effective drug for the treatment of glioblastoma, which can prolong the survival of glioblastoma patients by 2 to 5 months [9, 11,12,13]. Several molecular biomarkers, such as IDH mutation, 1p/19q co-deletion and MGMT promoter methylation, are shown to predict prognosis and/or drug responses for gliomas [3, 9, 13]. The overall prognosis of gliomas has not been improved effectively
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