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

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

  • J Hematol Oncol. 2021 Jul 10;14(1):109. doi: 10.1186/s13045-021-01124-z.
Rui-Chao Chai  # 1 2,  Yu-Zhou Chang  # 3 4,  Xin Chang 3 5 6,  Bo Pang 3 6,  Song Yuan An 4 6,  Ke-Nan Zhang 3 6,  Yuan-Hao Chang 3 6,  Tao Jiang 7 8 9,  Yong-Zhi Wang 10 11 12
Affiliations

Affiliations

  • 1 Department of Molecular Neuropathology, Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 Nan Si Huan Xi Road, Fengtai District, Beijing, 100050, China. [email protected].
  • 2 Chinese Glioma Genome Atlas Network (CGGA), Beijing, China. [email protected].
  • 3 Department of Molecular Neuropathology, Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 Nan Si Huan Xi Road, Fengtai District, Beijing, 100050, China.
  • 4 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 Nan Si Huan Xi Road, Fengtai District, Beijing, 100050, China.
  • 5 Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
  • 6 Chinese Glioma Genome Atlas Network (CGGA), Beijing, China.
  • 7 Department of Molecular Neuropathology, Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 Nan Si Huan Xi Road, Fengtai District, Beijing, 100050, China. [email protected].
  • 8 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 Nan Si Huan Xi Road, Fengtai District, Beijing, 100050, China. [email protected].
  • 9 Chinese Glioma Genome Atlas Network (CGGA), Beijing, China. [email protected].
  • 10 Department of Molecular Neuropathology, Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 Nan Si Huan Xi Road, Fengtai District, Beijing, 100050, China. [email protected].
  • 11 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 Nan Si Huan Xi Road, Fengtai District, Beijing, 100050, China. [email protected].
  • 12 Chinese Glioma Genome Atlas Network (CGGA), Beijing, China. [email protected].
  • # Contributed equally.
PMID: 34246306 DOI: 10.1186/s13045-021-01124-z
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.

Keywords

Glioblastoma; METTL3; N6,2′-O-Dimethyladenosine; NF-κB activation; YTHDF2.

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