Abstract
Intensive gene annotation has revealed many functional and regulatory elements in the human genome. Although eukaryotic protein-coding genes are generally transcribed into monocistronic mRNAs, recent studies have discovered additional short open reading frames (sORFs) in mRNAs. Here, we performed proteogenomic data mining for hidden proteins categorized into sORF-encoded polypeptides (SEPs) in human cancers. We identified a new SEP-encoding overlapping sORF (oORF) on the cell polarity determinant Scribble (SCRIB) that is considered a proto-oncogene with tumor suppressor function in Hippo-YAP/TAZ, MAPK/ERK, and PI3K/Akt/mTOR signaling. Reanalysis of clinical human proteomic data revealed translational dysregulation of both SCRIB and its oORF, oSCRIB, during carcinogenesis. Biochemical analyses suggested that the translatable oSCRIB constitutively limits the capacity of eukaryotic ribosomes to translate the downstream SCRIB. These findings provide a new example of cis-regulatory oORFs that function as a ribosomal roadblock and potentially serve as a fail-safe mechanism to normal cells for non-excessive downstream gene expression, which is hijacked in cancer.
Highlights
Intensive gene annotation has revealed many functional and regulatory elements in the human genome
Our study successfully demonstrated the existence of a new sORF-encoded polypeptides (SEPs)-encoding overlapping sORF (oORF) on the cell polarity-determining scaffold protein gene Scribble (SCRIB), which is considered a proto-oncogene with tumor suppressor function in antitumorigenic Hippo-YAP/TAZ, Ras/ Raf/MEK/ERK (MAPK/ERK), and PI3K/Akt/mTOR and proapoptotic c-Myc-induced signaling pathways[22,23,24,25,26,27,28,29]
Together with the results from our clinical human proteomic data reanalysis and biochemical analysis, we report that the translatable oORF on SCRIB, oSCRIB, is a cis-regulatory oORF potentially providing a fail-safe mechanism to normal cells for nonexcessive downstream SCRIB expression, whereas the mechanism was dysregulated in cancer cells for their survival and proliferation
Summary
Intensive gene annotation has revealed many functional and regulatory elements in the human genome. Eukaryotic protein-coding genes are generally transcribed into monocistronic mRNAs, recent studies have discovered additional short open reading frames (sORFs) in mRNAs. Here, we performed proteogenomic data mining for hidden proteins categorized into sORF-encoded polypeptides (SEPs) in human cancers. A combination of high-quality data on both proteomic mass spectra and genomic/transcriptomic nucleotide sequences (or ORFeomes) is indispensable for the more comprehensive identification of human proteomes[19,20,21] This proteogenomic approach still promises to uncover previously ignored dark proteomes and peptidomes, including novel SEPs. In this study, we performed proteogenomic data mining for hidden SEP-encoding genes in the human genome through the use of publicly available high-quality datasets of human cancer cell lines, which were obtained from MS-based proteomics and transcriptomic RNA sequencing (RNA-Seq). Together with the results from our clinical human proteomic data reanalysis and biochemical analysis, we report that the translatable oORF on SCRIB, oSCRIB, is a cis-regulatory oORF potentially providing a fail-safe mechanism to normal cells for nonexcessive downstream SCRIB expression, whereas the mechanism was dysregulated in cancer cells for their survival and proliferation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
