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

Abstract

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.

Mitochondrial outer membrane protein MTUS1/ATIP1 exerts antitumor effects through ROS-induced mitochondrial pyroptosis in head and neck squamous cell carcinoma

“…MTUS1 expression is downregulated in several types of malignancies, such as breast cancer 37 , colorectal carcinoma 38 and gastric cancer 39 . ATIP1, which is one of the major products of the MTUS1 gene, plays a pivotal role in the carcinogenesis of several malignancies 40 . Our previous study verified that HNSCC cells showed notably reduced ATIP1 expression 13 , 14 .…”

ATIP/ATIP1 regulates prostate cancer metastasis through mitochondrial dynamic-dependent signaling

“…In addition to ATIP3, ATIP1 also plays a role in tumor progression. Overexpression of ATIP1 interferes with tumor irradiation, therapy by increasing DNA damage repair in glioblastoma [30] . Our studies revealed that ATIP1 is responsible for PC3-cell-directed migration and invasion across Matrigel-coated inserts.…”

“… [30] found that ATIP1 expression was downregulated in malignant glioma, probably due to promoter hypermethylation. Furthermore, high ATIP1 expression might retard the response to radiation therapy by enhancing double-strand DNA break repair [30] . ATIP1 participates in p53-involved tumor signal transduction through binding between the ATIP1 promoter and p53 [31] .…”

Hypermethylation of tumor suppressor lncRNA MEF2C-AS1 frequently happened in patients at all stages of colorectal carcinogenesis

“…Promoter hypermethylation is identified to play an important role during tumorigenesis through silencing the gene expression of tumor suppressor genes [ 33 , 34 ]. Based on a genome-wide screening performed by Li Y et al, aberrant hypermethylation of α-internexin gene promoter was identified in both colon adenoma and cancer, and the findings were validated in biospecimens of 30 normal colons, 37 adenomas, and 30 colon cancers using quantitative methylation-specific PCR, and the silenced α-internexin expression by epigenetic alteration was confirmed in CRC cells [ 35 ].…”