The Journal of Clinical Investigation (Oct 2023)

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

  • Kang Li,
  • Jie Chen,
  • Caihua Zhang,
  • Maosheng Cheng,
  • Shuang Chen,
  • Wei Song,
  • Chunlong Yang,
  • Rongsong Ling,
  • Zhi Chen,
  • Xiaochen Wang,
  • Gan Xiong,
  • Jieyi Ma,
  • Yan Zhu,
  • Quan Yuan,
  • Qi Liu,
  • Liang Peng,
  • Qianming Chen,
  • Demeng Chen

Journal volume & issue
Vol. 133, no. 20

Abstract

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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 remain elusive. Here, we demonstrated that PCIF1-mediated cap mRNA m6Am modification promoted head and neck squamous cell carcinoma 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 that CTBP2 bound to similar mRNAs as compared with PCIF1. We then used the m6Am-Seq method to profile the mRNA m6Am site at single-base resolution and found that mRNA of TET2, a well-known tumor suppressor, was a major target substrate of the PCIF1-CTBP2 complex. Mechanistically, knockout of CTBP2 reduced PCIF1 occupancy on TET2 mRNA, and the PCIF1-CTBP2 complex negatively regulated the translation of TET2 mRNA. Collectively, our study demonstrates the oncogenic function of the epitranscriptome regulator PCIF1-CTBP2 complex, highlighting the importance of the m6Am modification in tumor progression.

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