Role of tumor suppressor MTUS1 ATIP1 in gliomagenesis Association with epigenetics and DNA repair

Abstract

Glioblastoma (GBM) is the most aggressive brain tumor in adults. Resistance mechanisms in newlineGBM present an array of challenges to understand its biology and to develop novel therapeutic newlinestrategies. Despite multidisciplinary treatments, overall survival remains poor in glioma newlinepatients. Although novel therapeutic approaches are being explored, no outstanding effects on newlinethe survival of GBM patients have been achieved so far. This substantiates the need to develop newlinenew therapeutic strategies. Hence, understanding glioma biology and the mechanisms newlineresponsible for its high malignancy is of central importance. In this regard, we have examined newlinethe impact of the tumor suppressor gene (TSG) MTUS1, coding for ATIP1, in glioma newlinemalignancy as well as how its expression might influence GBM therapy. MTUS1 has been newlinereported as a TSG in various cancers but there are no reports in glioma. We found that ATIP1 newlinewas significantly downregulated in high-grade glioma (HGG), GBM cells and GSC. In glioma newlinecells, ATIP1 mitigates proliferation, clonogenic outgrowth and is accompanied by cell motility newlinereduction and can be used as a biological marker to predict therapy outcomes. Glioma newlinespecimens, GBM cells and glioma stem cells (GSC) were analysed for ATIP1 expression by newlinePCR, immunoblot and immunohistology. In order to analyse the role of MTUS1 promotermethylation, newlineDecitabine treatment and bisulfite sequencing (BSS) were used. We found that in newlineHGG, decitabine treatment results in enhanced expression of ATIP1 and promoter methylation newlinemight play a crucial role in MTUS1 downregulation. In glioma-bearing mice, ATIP1 prolonged newlinethe overall and median survival. The effect of temozolomide (TMZ) and tumor irradiation on newlineATIP1 expression and its influence on survival were examined in vitro and in vivo. TMZ newlinetreatment recovered ATIP1 expression both in vitro and in vivo. However, surprisingly, newlineincreased ATIP1 expression resulted in an increased repair of irradiation-induced DNA damage newlineand protects GBM cells against cell death induced by irradiation. The impact