As such, our findings that SMYD3 functions as an activator and repressor in HPV-negative HNSCC are consistent with previous studies in other cancer types, showing that SMYD3 can act through different mechanisms, including the deposition of activating H3K4me3 and repressive H4K20me3 histone marks, to regulate the transcription of its target genes12,17–21. Here, SMYD3 is linked to cancer.