2. Academic Validation
  3. The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway

The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway

  • Cell Death Dis. 2024 Jun 3;15(6):390. doi: 10.1038/s41419-024-06736-0.
Jun-Jun Chen # 1 2,  Tian-Zhu Lu # 3 4,  Tao Wang 2,  Wen-Hui Yan 1 2,  Fang-Yan Zhong 3,  Xin-Hui Qu 5,  Xiao-Chang Gong 3 4,  Jin-Gao Li 3 4,  Fang-Fang Tou 6,  Li-Ping Jiang 1 7,  Xiao-Jian Han 8 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
  • 2 Institute of Geriatrics, Jiangxi Provincial People's Hospital & The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China.
  • 3 NHC Key Laboratory of Personalized Diagnosis and Treatment of Nasopharyngeal Carcinoma, Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, PR China.
  • 4 Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, PR China.
  • 5 The Second Department of Neurology, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China.
  • 6 Department of Oncology, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China.
  • 7 Key Laboratory of Drug Targets and Drug Screening of Jiangxi Province, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
  • 8 Institute of Geriatrics, Jiangxi Provincial People's Hospital & The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China. hanxiaojian@hotmail.com.
  • 9 Key Laboratory of Drug Targets and Drug Screening of Jiangxi Province, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China. hanxiaojian@hotmail.com.
  • # Contributed equally.
PMID: 38830885 DOI: 10.1038/s41419-024-06736-0
Abstract

Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA Sequencing and MeRIP Sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.

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