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PCIF1 can mediate the methylation of [N.sup.6],2'-O-dimethyladenosine ([m.sup.6]Am) in mRNA. Yet, the detailed interplay between PCIF1 and the potential cofactors and its pathological significance remain elusive. Here, we demonstrated that PCIF1mediated cap mRNA [m.sup.6]Am 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 [m.sup.6]Am deposition on mRNA. CLIP-Seq data demonstrated that CTBP2 bound to similar mRNAs as compared with PCIF1. We then used the [m.sup.6]Am-Seq method to profile the mRNA [m.sup.6]Am 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 [m.sup.6]Am modification in tumor progression., Introduction Recently, it has been increasingly evident that dysregulation of mRNA modifications and dysregulation of the modifiers are important factors in the aggressiveness and malignancy of tumors (1-4). Methylated modifications [...]