Small open reading frame-encoded protein production is modulated by nonsense-mediated decay in breast cancer - SUM159PT UPF1 Knockdonw Study

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.

由人类基因组编码的低丰度非经典蛋白质所衍生的肽段，可被主要组织相容性复合体（major histocompatibility complex, MHC）呈递，且可作为潜在新抗原或治疗靶点。然而，这类蛋白质在基因组中的分布频率尚不明确。本研究通过蛋白质基因组学方法，在乳腺癌细胞系中鉴定出数种非经典蛋白质。尽管可检测到这类蛋白质的存在，但其转录本与对应蛋白质均呈现低丰度特征，且表达模式存在不一致性。通过UPF1基因敲低靶向无义介导的mRNA降解（nonsense-mediated decay, NMD）通路，可同时提升非编码转录本与非经典蛋白质的表达水平，提示这类分子会受到细胞内保守质量控制机制的降解调控。本研究还观察到，与抗原呈递相关的未注释转录本及人类白细胞抗原（human leukocyte antigen, HLA）转录本的表达水平均有所上调。上述结果表明，UPF1可参与调控或抑制转录噪音；而调控UPF1的表达水平，能够扩充新抗原储备库并提升新抗原呈递效率，有望增强癌症的免疫治疗应答效果。