The adenovirus early region 1A (E1A) proteins were described originally as immortalizing oncoproteins that altered transcription in rodent cells. Surprisingly, the 243-amino-acid form of adenovirus-5 E1A was found subsequently to reverse-transform many human tumour cells. Tumour suppression apparently results from the ability of E1A to re-programme transcription in tumour cells, and the molecular basis of this intriguing effect is now beginning to emerge. These discoveries have provided a tool with which to study the regulation of fundamental cellular processes.

Human papillomavirus negative (HPV-) head and neck squamous cell carcinomas (HNSCC) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways including cell-signalling, cell-cycle and/or immune evasion in their development. Here, we analyze public datasets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% HPV-HNSCCs. Specifically, we identify novel recurrent p.K36M mutations occurring in multiple histone H3 genes. We further validate their presence in multiple independent HNSCC datasets and show that along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. H3K36M and NSD1 defects converge on altering H3K36 methylation, subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate surprisingly limited redundancy for NSD family members in HPV-HNSCCs and suggest a potential role of impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-HNSCCs driven by aberrant H3K36 methylation.

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