A positive feedback loop between YTHDC1 and EP300 drives multiple myeloma tumorigenesis

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.