The implication of non-AUG-initiated N-terminally extended proteoforms in cancer

Dysregulated translation is a hallmark of cancer, and recent genome-wide studies in tumour cells have uncovered widespread translation of non-canonical reading frames that often initiate at non-AUG codons. If an upstream non-canonical start site is located within a frame with an annotated coding sequence (CDS), such translation events can lead to the production of proteoforms with altered N-termini (PANTs). Certain examples of PANTs from oncogenes (e.g. c-MYC) and tumour suppressors (e.g. PTEN) have been previously linked to cancer. We have performed a systematic computational analysis on recently identified non-AUG initiation-derived N-terminal extensions of cancer-associated proteins, and we discuss how these extended proteoforms may acquire new oncogenic properties. We identified a loss of stability for the N-terminally extended proteoforms of oncogenes TCF-4 and SOX2. Furthermore, we discovered likely functional short linear motifs within the N-terminal extensions of oncogenes and tumour suppressors (SOX2, SUFU, SFPQ, TOP1 and SPEN/SHARP) that could provide an explanation for previously described functionalities or interactions of the proteins. In all, we identify novel cases where PANTs likely show different localization, functions, partner binding or turnover rates compared to the annotated proteoforms. Therefore, we propose that alterations in the stringency of translation initiation, often seen under conditions of cellular stress, may result in reprogramming of translation to generate novel PANTs that influence cancer progression.

翻译失调是癌症的标志性特征，近期在肿瘤细胞中开展的全基因组研究揭示了非经典阅读框的广泛翻译现象，这类翻译常起始于非AUG密码子。若上游非经典起始位点位于注释编码序列（CDS）的同一阅读框内，此类翻译事件可产生N端改变的蛋白亚型（PANTs）。此前已有研究表明，癌基因（如c-MYC）和抑癌基因（如PTEN）来源的某些PANTs与癌症相关。我们对近期鉴定的癌症相关蛋白的非AUG起始衍生N端延伸进行了系统计算分析，并探讨了这些延伸蛋白亚型可能获得的新致癌特性。我们发现癌基因TCF-4和SOX2的N端延伸蛋白亚型存在稳定性丧失现象。此外，我们还在癌基因和抑癌基因（SOX2、SUFU、SFPQ、TOP1及SPEN/SHARP）的N端延伸区中发现了可能具有功能的短线性基序，这些基序或可解释此前报道的蛋白功能或相互作用。综上，我们鉴定了若干新案例，其中PANTs与注释蛋白亚型相比，可能表现出不同的定位、功能、伙伴结合能力或周转率。因此，我们提出，细胞应激条件下常见的翻译起始严格性改变，可能导致翻译重编程，从而产生影响癌症进展的新型PANTs。