YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-κB and promote the malignant progression of glioma

Abstract

Background The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N6,2′-O-dimethyladenosine (m6A) reader, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas. Methods YTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2. Results YTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m6A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression. Conclusions Our findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m6A modification.

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

“…Glioma is one of the most common and highly aggressive primary brain tumors of the central nervous system [ 1 ]. According to their histological characteristics, gliomas are classified as astrocytomas, anaplastic astrocytomas, and glioblastomas [ 2 ].…”

RNA m1A Methyltransferase TRMT6 Predicts Poorer Prognosis and Promotes Malignant Behavior in Glioma

“…Additionally, correlation analysis showed that there were high correlations among m1A regulators, in particular between YTHDF2 and TRMT6 ( Supplementary Figures S3A–D ). Previous studies have identified YTHDF2 as a cancer-promoting gene in glioma ( Chai et al, 2021 ). Moreover, subgroup survival analysis indicated that overexpression of TRMT6 was closely associated with poorer prognosis in both YTHDF2 low- and high-expression patients ( Supplementary Figures S3E–H ).…”

“…Many studies have demonstrated that overexpression of YTHDF2 was significantly associated with higher malignant grades and a worse prognosis in glioma. Meanwhile, in vivo and in vitro experiments have confirmed that upregulated YTHDF2 facilitated the malignant progression of glioma (Chai et al, 2021). However, until now, there has been only one report addressing the function of TRMT6 in glioma.…”

MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas

“…The IDH -wildtype GBM cell line, N33, was extracted from fresh glioma of a female patient shortly after surgery in Beijing Tiantan Hospital. 13 Patient-derived N33 cell lines have been authenticated after stable passage. The short tandem repeat analysis indicated that N33 was not cross-contaminated with other human cell lines and did not have a 100% match with any cell line in the ATCC (American Type Culture Collection) or DSMZ (German Collection of Microorganisms and Cell Cultures) database.…”