PCIF1能够介导mRNA中N6,2'-O-二甲基腺苷(m6Am)的甲基化。然而，PCIF1与潜在辅因子之间的详细相互作用以及其病理意义仍然不清楚。在这里，我们证明了PCIF1介导的mRNA帽子m6Am修饰促进了头颈鳞状细胞癌（HNSCC）的体外和体内进展。CTBP2被确定为PCIF1的辅因子，用于催化mRNA上的m6Am沉积。CLIP-seq数据证明CTBP2与PCIF1结合到相似的mRNA上。然后，我们利用了m6Am-seq方法以单碱基分辨率分析mRNA上的m6Am位点，并发现TET2 mRNA，一个众所周知的抑癌基因，是PCIF1-CTBP2复合物的主要靶底物。机制上，CTBP2的缺失减少了PCIF1在TET2 mRNA上的占有率，PCIF1-CTBP2复合物负调节了TET2 mRNA的翻译。总之，我们的研究证明了表观转录组调节因子PCIF1-CTBP2复合物的致癌功能，突出了m6Am修饰在肿瘤进展中的重要性。

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.