Regulation of Non-Canonical Proteins Encoded by Small Open Reading
Frames via the Nonsense-Mediated Decay Pathway
Abstract
Immunotherapy harnesses neoantigens encoded within the human genome, but
their therapeutic potential is hampered by low expression, which may be
controlled by the Nonsense-Mediated Decay (NMD) pathway. This study
investigates the impact of UPF1-knockdown on the expression of
non-canonical/mutant proteins, employing proteogenomic to explore UPF1
role within the NMD pathway. Additionally, we conducted a comprehensive
pan-cancer analysis of UPF1 expression and evaluated UPF1 expression in
Triple-Negative Breast Cancer (TNBC) tissue in-vivo. Our findings reveal
that UPF1-knockdown leads to increased transcription of
non-canonical/mutant proteins, particularly those originating from
retained-introns, pseudogenes, long non-coding RNAs, and unannotated
transcript biotypes. Moreover, our analysis demonstrates elevated UPF1
expression in various cancer types, with notably heightened protein
levels in patient-derived TNBC tumours compared to adjacent tissues.
This study elucidates UPF1 role in mitigating transcriptional noise by
degrading transcripts encoding non-canonical/mutant proteins.
Intriguingly, we observe an upregulation of the NMD pathway in cancer,
potentially acting as a “neoantigen-masking” mechanism that suppresses
non-canonical/mutant protein expression. Targeting this mechanism may
reveal a new spectrum of neoantigens accessible to the antigen
presentation pathway. Our novel findings provide a strong foundation for
the development of therapeutic strategies aimed at targeting UPF1 or
modulating the NMD pathway.