The Tumor Suppressor MTUS1/ATIP1 Modulates Tumor Promotion in Glioma: Association with Epigenetics and DNA Repair

Simple Summary Despite multidisciplinary treatments, survival remains poor in glioma patients. Although novel therapeutic approaches are being explored, no outstanding effects on the survival have been achieved so far, which substantiates the need to develop new therapeutic strategies. To understand the mechanisms responsible for its high malignancy and obligatory recurrence, we examined the impact of MTUS1, a tumor-suppressor gene (TSG), coding for ATIP1, in glioma malignancy as well as how its expression might influence glioma therapy. We confirmed that in glioma cells, elevated ATIP1 expression damps tumor progression by mitigating proliferation and motility. Additionally, MTUS1/ATIP1 can be used as a biological marker to predict therapy outcomes. In glioma cell lines, glioma sphere cultures (GSC), high-grade glioma (HGG) and especially in glioma recurrence, MTUS1/ATIP1 expression is downregulated, probably by promoter hypermethylation. However, in GBM, high ATIP1 expression might interfere with radiation-therapy since elevated expression of MTUS1/ATIP1 drives double-strand break (DSB) DNA repair. Glioblastoma (GBM) is a highly aggressive brain tumor. Resistance mechanisms in GBM present an array of challenges to understand its biology and to develop novel therapeutic strategies. We investigated the role of a TSG, MTUS1/ATIP1 in glioma. Glioma specimen, cells and low passage GBM sphere cultures (GSC) were analyzed for MTUS1/ATIP1 expression at the RNA and protein level. Methylation analyses were done by bisulfite sequencing (BSS). The consequence of chemotherapy and irradiation on ATIP1 expression and the influence of different cellular ATIP1 levels on survival was examined in vitro and in vivo. MTUS1/ATIP1 was downregulated in high-grade glioma (HGG), GSC and GBM cells and hypermethylation at the ATIP1 promoter region seems to be at least partially responsible for this downregulation. ATIP1 overexpression significantly reduced glioma progression by mitigating cell motility, proliferation and facilitate cell death. In glioma-bearing mice, elevated MTUS1/ATIP1 expression prolonged their survival. Chemotherapy, as well as irradiation, recovered ATIP1 expression both in vitro and in vivo. Surprisingly, ATIP1 overexpression increased irradiation-induced DNA-damage repair, resulting in radio-resistance. Our findings indicate that MTUS1/ATIP1 serves as TSG-regulating gliomagenesis, progression and therapy resistance. In HGG, higher MTUS1/ATIP1 expression might interfere with tumor irradiation therapy.

Automated summary

Despite various treatments, survival rates for glioma patients are low. The tumor-suppressor gene MTUS1/ATIP1 may play a role in glioma malignancy and treatment outcomes, with its expression potentially being controlled by DNA methylation. Overexpression of ATIP1 can suppress glioma progression.