Yifan Hou, Qiqi Shen, Jianwei Qu, Enfan Zhang, Ruyi Xu, Huiyao Gu, Wen Cao, Haoguang Chen, Jinna Zhang, Shunnan Yao, Zhenfeng Dai, Hongying Ye, Chunting Zhu, Yunlu Jia, Jingsong He, Pengxu Qian, Zhen Cai
N6-methyladenosine (m6A), the most prevalent internal RNA modification in mammals, regulates key cellular processes through writer, eraser, and reader proteins. Recent studies have emerged that dysregulation of m6A modifiers promotes tumorigenesis by altering RNA metabolism. However, the role of m6A in multiple myeloma (MM) remains enigmatic. Here, we identify YTHDC1, a nuclear m6A reader, as a key oncogenic factor in MM. YTHDC1 is upregulated in MM cells and associated with poor prognosis. Functional studies reveal that YTHDC1 facilitates MM cell growth and survival in an m6A-dependent manner. Mechanistically, YTHDC1 directly binds m6A-modified EP300 mRNA and enhances its stability and expression. In turn, p300 activates YTHDC1 transcription via H3K27ac deposition and IRF3/IRF4 recruitment, establishing a self-reinforcing feedback loop. This interplay between RNA m6A methylation and histone H3K27 acetylation contributes to MM pathogenesis. Our findings highlight the YTHDC1-EP300 axis as a promising target for therapeutic intervention.