Deep computational analysis details dysregulation of eukaryotic translation initiation complex eIF4F in human cancers

eIF4F plays diverse roles in human cancers, which complicate the development of an overarching understanding of its functional and regulatory impacts across tumor types. Typically, eIF4F drives initiation from the mRNA 5' end (cap) and is composed of eIF4G1, eIF4A1, and cap-binding eIF4F. Cap-independent initiation is possible without eIF4E, from internal ribosomal entry sites (IRESs). By analyzing large public datasets, we found that cancers selectively overexpress EIF4G1 more than EIF4E. That expression imbalance supports EIF4G1 as a prognostic indicator in patients with cancer, It also attenuates housekeeping pathways that are usually regulated in a tissue-specific manner via cap-dependent initiation in healthy tissues and reinforce regulation of cancer-preferred pathways in cap-independent contexts. Cap-independent initiation is mechanistically attributable to eIF4G1 hyperphosphorylation that promotes binding to eIF4A1 and reduced eIF4E availability. Collectively, these findings reveal a novel model of dysregulated eIF4F function and highlight the clinical relevance of cap-(in)dependent initiation in cancer.

Automated summary

eIF4F plays diverse roles in human cancers, with overexpression of EIF4G1 being more selective than EIF4E, serving as a prognostic indicator in cancer patients. This expression imbalance affects housekeeping pathways and cancer-related pathways, leading to cap-independent initiation due to eIF4G1 hyperphosphorylation. These findings provide a novel model of dysregulated eIF4F function and highlight the clinical relevance of cap-(in)dependent initiation in cancer.