We herein identify two dysregulated transcription cascades that contribute to NPC tumorigenesis: (1) DNA methylation of HOXA2 impairs the binding of transcription activator p300 on the HOXA2 promoter; (2) the inactivation of HOXA2 promotes TBP binding on MMP-9 promoter and activates the MMP-9 expression. Here, EP300 is linked to nasopharyngeal carcinoma.