Small open reading frame-encoded protein production is modulated by nonsense-mediated decay in breast cancer - MDAMB453

Peptides from low abundance non-canonical proteins encoded by the human genome are presented by the major histocompatibility complex and serve as potential neoantigens or therapeutic targets. However, their prevalence in the genome is unclear. We identified several non-canonical proteins produced by breast cancer cell lines using proteogenomics approach. Although these proteins were detectable, the transcripts and corresponding proteins showed low abundance and inconsistent expression pattern. Targeting the nonsense-mediated decay pathway by UPF1-knockdown increased the levels of both non-coding transcripts and non-canonical proteins, suggesting they are subjected to degradation by conserved quality control mechanisms in cells. We also observed increased expression of unannotated transcripts and human leukocyte antigen transcripts associated with antigen presentation. These observations suggest that UPF1 has a role in regulating or suppressing transcriptional noise and that modulating the expression level of UPF1 could expand the reservoir of neoantigens and increase neoantigen presentation, potentially augmenting immunotherapeutic responses in cancers.