The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma

  • J Clin Invest. 2023 Aug 29;e170173. doi: 10.1172/JCI170173.
Kang Li  1 ,  Jie Chen  2 ,  Caihua Zhang  1 ,  Maosheng Cheng  1 ,  Shuang Chen  1 ,  Wei Song  3 ,  Chunlong Yang  1 ,  Rongsong Ling  4 ,  Zhi Chen  1 ,  Xiaocheng Wang  1 ,  Gan Xiong  1 ,  Jieyi Ma  1 ,  Yan Zhu  1 ,  Quan Yuan  3 ,  Qi Liu  5 ,  Liang Peng  6 ,  Qianming Chen  7 ,  Demeng Chen  1
Affiliations
  • 1. Otorhinolaryngology Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2. Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
  • 3. State Key Laboratory of Oral Diseases, Sichuan University, chengdu, China.
  • 4. Institute for Advanced Study, Shenzhen University, Shenzhen, China.
  • 5. Rice Research Institute, Key Laboratory of Genetics and Breeding of High Quality Rice in Southern China, Guangzhou, China.
  • 6. Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China.
  • 7. Stomatology Hospital, Zhejiang University School of Medicine, Guangzhou, China.
PMID: 37643007 DOI: 10.1172/JCI170173
Abstract

PCIF1 can mediate the methylation of N6,2'-O-dimethyladenosine (m6Am) in mRNA. Yet, the detailed interplay between PCIF1 and the potential cofactors and its pathological significance remains elusive. Here, we demonstrated that PCIF1-mediated cap mRNA m6Am modification promoted head and neck squamous cell carcinoma (HNSCC) progression both in vitro and in vivo. CTBP2 was identified as a cofactor of PCIF1 to catalyze m6Am deposition on mRNA. CLIP-seq data demonstrated CTBP2 bound to similar mRNAs as PCIF1. We then utilized m6Am-seq method to profile mRNA m6Am site at single-base resolution and found mRNA of TET2, a well-known tumor suppressor, was a major target substrate of PCIF1-CTBP2 complex. Mechanistically, knockout of CTBP2 reduced PCIF1 occupancy on TET2 mRNA and PCIF1-CTBP2 complex negatively regulated the translation of TET2 mRNA. Collectively, our study demonstrated the oncogenic function of the epitranscriptome regulator PCIF1-CTBP2 complex, highlighting the importance of the m6Am modification in tumor progression.

Keywords
Cell Biology; Epigenetics; Head and neck cancer; Oncology.
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